JP2021532183A - PEGylated prodrug of phenolic TRPV1 agonist - Google Patents

Abstract

This specification describes compounds for regulating transient receptor potential vanilloid 1 receptor (TRPV1) activity, pharmaceutical compositions and agents containing the compounds, and methods of using the compounds. [Selection diagram] Fig. 1

Description

Cross-reference This application claims the benefit of US Provisional Patent Application No. 62 / 711,361 filed July 27, 2018, which is cited herein by reference in its entirety. NS.

This specification describes compounds for regulating transient receptor potential vanilloid 1 receptor (TRPV1) activity, pharmaceutical compositions and agents containing the compounds, and methods of using the compounds.

In one aspect, the present specification describes a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a hydrate.

式中、
Ｙはフェノール性ＴＲＰＶ１アゴニストであり、ここでフェノール性水酸基の水素原子は、

During the ceremony
Y is a phenolic TRPV1 agonist, where the hydrogen atom of the phenolic hydroxyl group is

との共有結合により置き換えられ、
Ｒ_１は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_２は、−（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）（ＣＨ_２）_ｍＯ（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｏ（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｎ（Ｒ_４）（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｒ_５、−Ｃ（Ｏ）ＯＲ_５、または−Ｃ（Ｏ）Ｎ（Ｒ_４）（Ｒ_５）であり、
Ｒ_３は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_４は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_５はＣ_１−Ｃ_５０アルキルであり、
ｍは１〜１０であり、
ｎは１〜５０であり、ならびに
ｐは１〜９である。

Replaced by a covalent bond with
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is-(CH _{2 CH 2} O) _n R ₃ , -C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) ) _N R ₃ , -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ , -C (O) R ₅ , -C (O) OR ₅ , or -C (O) N ( R ₄ ) (R ₅ ),
R ₃ is hydrogen or C _1- C ₆ alkyl,
R ₄ is hydrogen or _C 1 -C ₆ alkyl,
R ₅ is C _1- C ₅₀ alkyl and is
m is 1 to 10
n is 1 to 50, and p is 1 to 9.

In some embodiments, it is a compound of formula (I), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ , −C (O) (CH ₂ ) _m O (CH ₂ CH). ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) _n R ₃ , or -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), wherein m is 1-5. In some embodiments, it is a compound of formula (I), wherein m is 2. In some embodiments, it is a compound of formula (I), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, a compound of formula (I), wherein, R ₄ is hydrogen. In some embodiments, a compound of formula (I), wherein, _{R 4} is _C 1 -C ₆ alkyl. In some embodiments, a compound of formula (I), wherein, R ₃ is hydrogen. In some embodiments, a compound of formula (I), wherein, _{R 3} is _C 1 -C ₆ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₃ is −CH ₃ . In some embodiments, it is a compound of formula (I), wherein n is 1-30. In some embodiments, it is a compound of formula (I), wherein n is 2-20. In some embodiments, it is a compound of formula (I), wherein n is 2-12. In some embodiments, it is a compound of formula (I), wherein n is 4-10. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) N (R ₄ ) (R ₅ ). In some embodiments, a compound of formula (I), wherein, _{R 5} is _C 1 _{-C 25} alkyl. In some embodiments, a compound of formula (I), wherein, _{R 5} is _C 1 _{-C 10} alkyl. In some embodiments, a compound of formula (I), wherein, _{R 5} is _C 1 -C ₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₅ is −CH ₃ . In some embodiments, a compound of formula (I), wherein, _{R 1} is _C 1 -C ₆ alkyl. In some embodiments, a compound of formula (I), wherein, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (I), wherein R ₁ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), wherein R ₁ is hydrogen. In some embodiments, it is a compound of formula (I), where p is 1. In some embodiments, it is a compound of formula (I), where p is 2.

In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６は独立して、水素、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択され、Ｊは−ＮＨＣ（Ｏ）Ｒ_７または−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。別の実施形態では、式（Ｉ）の化合物であって、式中、Ｊは−ＮＨＣ（Ｏ）Ｒ_７である。別の実施形態では、式（Ｉ）の化合物であって、式中、Ｊは−Ｃ（Ｏ）ＯＲ_７である。別の実施形態では、式（Ｉ）の化合物であって、式中、Ｒ_７は非置換のＣ_１−Ｃ_１２アルキルである。別の実施形態では、式（Ｉ）の化合物であって、式中、Ｒ_６はＣ_１−Ｃ_６アルコキシである。別の実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is independently hydrogen, halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC. _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl , C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl, C _1- C ₉ heteroaryl, C ₆ -C _{10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl _sulfoxide, C 6 _{-C 10} aryl _sulfoxide, C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} Selected from aryl sulfones, J is -NHC (O) R ₇ or -C (O) OR ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N ( CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C ₃ −C ₈ cycloalkyl, C _{1 −} C ₆ fluoroalkyl, C _{1 −} C ₆ heteroalkyl, C _{1 −} C ₆ alkoxy, C _{1 −} C ₆ fluoroalkoxy, C _{2 −} C ₉ heterocyclo _alkyl, C 6 _{-C 10 aryl,} C 1 -C _{9 heteroaryl,} C 6 _{-C 10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl sulfoxide, _{C 6} - C ₁₀ aryl _{sulfoxide, C} 1 -C ₁ being optionally substituted with C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} 1 or more groups selected from arylsulfonic It is _{2 alkyl.} In another embodiment, it is a compound of formula (I), wherein J is −NHC (O) R ₇ . In another embodiment, it is a compound of formula (I), in which J is −C (O) OR ₇ . In another embodiment, it is a compound of formula (I), wherein R ₇ is an unsubstituted C _1- C ₁₂ alkyl. In another embodiment, a compound of formula (I), wherein, _{R 6} is _C 1 -C ₆ alkoxy. In another embodiment, the compound of formula (I), wherein Y is

である。別の実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

Is. In another embodiment, the compound of formula (I), wherein Y is

である。

Is.

In some embodiments, there are compounds having the following structures, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, or hydrates thereof.

In some embodiments, there are compounds having the following structures, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, or hydrates thereof.

In another embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate or hydrate, and a pharmaceutically acceptable diluent, excipient. , Or a pharmaceutical composition comprising a binder is provided.

In another embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate or hydrate, and a pharmaceutically acceptable diluent, excipient. , Or a pharmaceutical composition comprising a binder is provided. In some embodiments, the pharmaceutical composition comprises intravenous injection, epidural injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, perineural injection, cerebrospinal injection, intraarticular injection, oral administration, Or formulated for topical administration.

In another aspect, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable. It comprises a step of administering a solvate or a hydrate to the subject. In some embodiments, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable. The pain is associated with cancer, comprising the step of administering to the subject a possible solvate or hydrate.

The time course of the plasma concentration (ng / mL) of capsaicin after epidural dosing of compounds 1, 2, 3, 4, and 7 in rats is shown. The time course of the plasma concentration (ng / mL) of cyclic urea resulting from the administration of Compounds 1, 2, 3, 4, and 7 in rats is shown. The time course of cerebrospinal fluid (CSF) concentration (μM) of cyclic urea resulting from administration of Compounds 1, 2, 3, 4, and 7 in rats is shown.

Capsaicin is the main component that causes the pungent taste of chili peppers, and is an alkaloid found in the genus Capsicum. Capsaicin is an 8-methyl-N-vanillyl-6-nonenamide, a ligand-gated type that is a transient receptor potential vanilloid 1 receptor (TRPV1; formerly known as vanilloid receptor 1 (VR1)). It is a highly selective agonist for non-selective cation channels. TRPV1 is preferentially expressed on small-diameter sensory neurons, especially A and C fibers dedicated to the detection of pain and adverse sensations. TRPV1 responds to adverse stimuli, including capsaicin, heat, and extracellular acidification, and integrates co-exposure to these stimuli. (Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci. 2001.24: 487-517).

Although TRPV1 agonists such as capsaicin have been shown to reduce pain in a variety of environments, there are problems associated with their use. The initial effects of TRPV1 expression (capsaicin sensitivity) nociceptor activation are burning sensation, hyperalgesia, allodynia, and erythema. However, after long-term exposure to low-concentration capsaicin, or a single exposure to high-concentration capsaicin or other TRPV1 agonists, small-diameter sensory axons become less sensitive to various stimuli, including capsaicin or thermal stimuli. .. This long-term exposure is also characterized by a reduced pain response. Such late-stage effects of capsaicin, often referred to as "desensitization," are the rationale for producing capsaicin formulations for the treatment of various pain syndromes and other illnesses. (Bley, KR Recept developments in transient receptor potential vanilloid receptor 1 agonist-based therapies. Expert Opin Invest 1345.

In addition, TRPV1 agonists such as capsaicin have very limited water solubility and are very potent stimulants that require special equipment for handling. Due to its limited water solubility, it is not easily mixed with ordinary drugs obtained as an aqueous solution. Therefore, delivery of TRPV1 agonists such as capsaicin in significant amounts requires the use of non-aqueous formulations. Such formulations often do not fit current practices / procedures specifically in terms of sterile aqueous solutions used in surgery. In addition, because capsaicin has a strong ability to cause irritation, it is desirable to utilize a water-soluble prodrug of capsaicin that minimizes the activity of capsaicin until the prodrug reaches the desired active site.

In some embodiments, the present specification describes a prodrug suitable for parenteral administration, wherein the prodrug is in an aqueous solution state at a pH suitable for parenteral administration (eg, pH 4.5 ± 1.0). It has stability, which allows a reasonable amount of time to retain / manipulate the dose formulation of the prodrug prior to administration without causing a substantial conversion of the powerful drug, including but not limited to capsaicin. A frame (eg 0-4 hours) is provided. Described herein are capsaicin prodrugs that demonstrate stability in aqueous solutions at pH suitable for parenteral administration, including but not limited to pH 4.5.

Finally, the introduction of PEG moieties of various lengths into the prodrug provides an opportunity to regulate the physiochemical and pharmacokinetic properties of the converted prodrug and the resulting cyclic urea. In some embodiments, adjustment of the pharmacokinetic profile of the prodrug and the resulting cyclic urea is involved in reducing the CSF permeability of the cyclic urea after epidural administration of the prodrug.

Therefore, in some embodiments, it is desirable to provide a TRPV1 agonist prodrug with the following characteristics: 1) Increased water solubility (to capsaicin) makes it generally possible to inject into the intended site of action. It is desirable to provide a TRPV1 agonist prodrug that is soluble in the aqueous / sterile injectable formulation used in; 2) the irritation associated with administration of the TRPV1 agonist may be reduced or delayed; 3) rapid delivery. (TRPV1 agonist delivery has a half-life of less than 30 minutes, more preferably less than 15 minutes); 4) to prodrugs, especially at pH suitable for parenteral administration (eg pH 4.5 ± 1.0). Demonstrate desirable aqueous state stability, and finally 5) a modified pharmacokinetic profile for the non-PEGylated prodrug and the resulting cyclic urea (eg, reduced CSF exposure of the cyclic urea corresponding to the prodrug). Prodrugs and the resulting cyclic urea. In addition, in some embodiments, it is desirable to deliver another pharmacologically active compound with a TRPV1 agonist prodrug, such as, but not limited to, a local anesthetic.

Accordingly, the compounds described herein are directed to novel water-soluble prodrugs of TRPV1 agonists, and methods of their synthesis and use. These TRPV1 agonist prodrugs are rapidly converted to active parent compounds when exposed to physiological conditions. The compounds described herein are significantly more hydrophilic / water soluble than their parent drug (eg, capsaicin) and are therefore well integrated into aqueous formulations. A method described herein of increasing the water solubility of capsaicin, its analogs, and other TRPV1 agonists by modifying the chemical structure of the parent molecule with a hydrophilic moiety (eg, a PEG moiety). In some embodiments described herein, the introduction of basic moieties that can be protonated under acidic conditions increases the solubility of the TRPV1 prodrug. The prodrugs described herein are such that after the prodrug has been delivered to the body and / or subjected to physiological conditions, the parent drug is released at a well-defined rate via a cyclization release reaction. Designed. The chemical release kinetics of the parent drug may provide two important properties: (a) reduction and / or delay in irritation that may occur due to avoidance of rapid delivery of high doses of TRPV1 agonists, and (b) specific pharmacological activity. / Rapid or delayed release of the parent TRPV1 agonist from the prodrug for adjustment of results. In some embodiments, such structural modifications are formulated or to 1) adapt many TRPV1 agonists / capsaicinoids that are very poorly water soluble, and 2) reduce the acute irritation associated with administration of the TRPV1 agonist. Eliminate dependence on specific requirements of the delivery device. In addition, water-soluble prodrugs are desirable when co-delivering other agents, especially when administering multiple sterile agents by injection.

In addition, in some embodiments, PEG moieties have been introduced to regulate both the physiochemical and pharmacokinetic properties of the prodrug and the resulting cyclized cyclic urea. The introduction of the PEG moiety takes into account the possibility of regulating the pharmacokinetics of both the prodrug and the resulting cyclic urea by the following abilities: 1) modification of overall size and polarity, and 2) "foundation". (Eg non-PEGylated) Increased molecular weight from prodrug / cyclic urea. As the size or length of the PEG group increases, there is a corresponding effect on the solubility of the prodrug in the aqueous medium. In addition to its effect on water solubility, the increased length of the attached PEG chain allows the prodrug and cyclic urea to access certain biological barriers (eg, the blood-brain barrier or CSF), thereby providing their pharmacokinetic properties. The ability to modify can be adjusted.

The capsaicin, capsaicinoids, or other TRPV1 agonist prodrugs described herein regulate the rate at which capsaicin, capsaicinoids, or other TRPV1 agonists become available to the body through a PH-regulated intramolecular cyclization release reaction. To be chemically modified. In some embodiments, the TRPV1 agonist prodrugs described herein are stable for long periods of time at pH values suitable for the manufacture of pharmaceutical formulations, but in vivo (under physiological conditions) in a well-controlled manner. It is converted rapidly. After parenteral administration, the compound of formula (I) or (II) is converted to the parent drug (TRPV1 agonist) via a temperature and pH regulated cyclization release reaction. The rate at which the prodrug is converted is determined by the cyclization release reaction, which can be modified by the addition of buffer. In some embodiments, the buffer can provide a time window in which turnover to the parent drug is significantly delayed until the physiological conditions are restored. In the embodiments described herein, the parent drug is released by intramolecular cyclization with an amine:

_{In some embodiments, the cyclization rate (t 1/2} ) of the compound of formula (I) or (II) at 37 ° C., pH 7.4 is 10 seconds to 10 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 10 seconds to 1 hour. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 10 seconds to 30 minutes. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 1 minute to 10 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 1 to 30 minutes. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 2-30 minutes. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 5-30 minutes. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 2 to 15 minutes. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 5 to 15 minutes. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 15 minutes to 2 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 15 minutes to 1.5 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 15 minutes to 1 hour. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 30 minutes to 2 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 30 minutes to 1.5 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 30 minutes to 1 hour. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 1 to 4 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 1 to 3 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 1 to 2 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 2 to 10 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 2 to 6 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 2 to 4 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 2 to 3 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 3-5 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 4 to 6 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 5 to 7 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 6-8 hours. In some embodiments, the cyclization rate (t _1/2 ) at 37 ° C. and pH 7.4 is 7-9 hours. In some embodiments, the cyclization rate (t1 / 8) at 37 ° C. and pH 7.4 is 8 to 10 hours.

Compounds In another embodiment, the present specification describes compounds having the structure of formula (I), or pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, or hydrates thereof. ,

式中、
Ｙはフェノール性ＴＲＰＶ１アゴニストであり、ここでフェノール性水酸基の水素原子は、

During the ceremony
Y is a phenolic TRPV1 agonist, where the hydrogen atom of the phenolic hydroxyl group is

との共有結合により置き換えられ、
Ｒ_１は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_２は、−（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）（ＣＨ_２）_ｍＯ（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｏ（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｎ（Ｒ_４）（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｒ_５、−Ｃ（Ｏ）ＯＲ_５、または−Ｃ（Ｏ）Ｎ（Ｒ_４）（Ｒ_５）であり、
Ｒ_３は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_４は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_５はＣ_１−Ｃ_５０アルキルであり、
ｍは１〜１０であり、
ｎは１〜５０であり、ならびに
ｐは１〜９である。

Replaced by a covalent bond with
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is-(CH _{2 CH 2} O) _n R ₃ , -C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) ) _N R ₃ , -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ , -C (O) R ₅ , -C (O) OR ₅ , or -C (O) N ( R ₄ ) (R ₅ ),
R ₃ is hydrogen or C _1- C ₆ alkyl,
R ₄ is hydrogen or _C 1 -C ₆ alkyl,
R ₅ is C _1- C ₅₀ alkyl and is
m is 1 to 10
n is 1 to 50, and p is 1 to 9.

In some embodiments, it is a compound of formula (I), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ , −C (O) (CH ₂ ) _m O (CH ₂ CH). ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) _n R ₃ , or -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ .

In some embodiments, it is a compound of formula (I), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₃ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is − CH ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is − CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. It is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. It is C _1- C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. It is a C _1- C ₃ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. -CH ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. -CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₆ It is alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₃ It is alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is -C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is -CH ₃ . .. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −CH ₂ CH ₃ Is.

In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. Is. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. in and, _{R 4} is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. in and, _{R 4} is _C 1 -C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₆ alkyl and R ₄ is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₆ alkyl and R ₄ is C _1- C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₃ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₃ alkyl and R ₄ is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₃ alkyl and R ₄ is C _1- C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. It is CH _3. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. CH ₃ and R ₄ are hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. is CH _{3, R 4} is _C 1 -C ₆ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. CH ₂ CH ₃ In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. CH ₂ CH ₃ and R ₄ is hydrogen. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. a CH ₂ CH _{3, R 4} is _C 1 -C ₆ alkyl.

In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₄₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₄₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₃₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is —C (O) R ₅ and R ₅ is C ₁ −C ₃₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₂₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₂₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is —C (O) R ₅ and R ₅ is C ₁ −C ₁₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₁₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is —C (O) R ₅ and R ₅ is C ₁ −C ₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) R ₅ and R ₅ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), wherein R ₂ is -C (O) R ₅ and R ₅ is -CH ₃ .

In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₄₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₄₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₃₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₃₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₂₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₂₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is —C (O) OR ₅ and R ₅ is C ₁ −C ₁₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₁₀ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is —C (O) OR ₅ and R ₅ is C ₁ −C ₅ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) OR ₅ and R ₅ is −CH ₃ .

In some embodiments, it is a compound of formula (I), wherein R ₂ is −C (O) N (R ₄ ) (R ₅ ). In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. a C ₁ -C ₄₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. a C ₁ -C ₄₀ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. a C ₁ -C ₃₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₃₀ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₂₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₂₀ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₁₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₁₀ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is a C _1- C ₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. -CH ₃ .

In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 45} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 40} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 35} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 30} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 25} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 20} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 15} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 10} alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 -C ₅ alkyl. In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. Yes, R ₅ is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. Yes, R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ), R ₄ is -CH ₃ and R. ₅ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ), R ₄ is -CH ₃ and R. ₅ is −CH ₃ .

In some embodiments, it is a compound of formula (I), wherein m is 1-5. In some embodiments, it is a compound of formula (I), wherein m is 2-10. In some embodiments, it is a compound of formula (I), wherein m is 4-10. In some embodiments, it is a compound of formula (I), wherein m is 2-8. In some embodiments, it is a compound of formula (I), wherein m is 2-6. In some embodiments, it is a compound of formula (I), wherein m is 2-4. In some embodiments, it is a compound of formula (I), wherein m is 1. In some embodiments, it is a compound of formula (I), wherein m is 2. In some embodiments, it is a compound of formula (I), wherein m is 3. In some embodiments, it is a compound of formula (I), wherein m is 4. In some embodiments, it is a compound of formula (I), wherein m is 5. In some embodiments, it is a compound of formula (I), wherein m is 6. In some embodiments, it is a compound of formula (I), wherein m is 7. In some embodiments, it is a compound of formula (I), wherein m is 8. In some embodiments, it is a compound of formula (I), wherein m is 9. In some embodiments, it is a compound of formula (I), wherein m is 10.

In some embodiments, it is a compound of formula (I), wherein n is 1-45. In some embodiments, it is a compound of formula (I), wherein n is 1-40. In some embodiments, it is a compound of formula (I), in which n is 1-35. In some embodiments, it is a compound of formula (I), wherein n is 1-30. In some embodiments, it is a compound of formula (I), wherein n is 1-25. In some embodiments, it is a compound of formula (I), wherein n is 1-20. In some embodiments, it is a compound of formula (I), wherein n is 2-20. In some embodiments, it is a compound of formula (I), wherein n is 2-16. In some embodiments, it is a compound of formula (I), wherein n is 2-12. In some embodiments, it is a compound of formula (I), where n is 2-10. In some embodiments, it is a compound of formula (I), wherein n is 4-10. In some embodiments, it is a compound of formula (I), wherein n is 3-12. In some embodiments, it is a compound of formula (I), where n is 1. In some embodiments, it is a compound of formula (I), where n is 2. In some embodiments, it is a compound of formula (I), where n is 3. In some embodiments, it is a compound of formula (I), where n is 4. In some embodiments, it is a compound of formula (I), where n is 5. In some embodiments, it is a compound of formula (I), where n is 6. In some embodiments, it is a compound of formula (I), where n is 7. In some embodiments, it is a compound of formula (I), where n is 8. In some embodiments, it is a compound of formula (I), where n is 9. In some embodiments, it is a compound of formula (I), where n is 10. In some embodiments, it is a compound of formula (I), where n is 11. In some embodiments, it is a compound of formula (I), where n is 12. In some embodiments, it is a compound of formula (I), where n is 13. In some embodiments, it is a compound of formula (I), where n is 14. In some embodiments, it is a compound of formula (I), where n is 15. In some embodiments, it is a compound of formula (I), where n is 16.

In some embodiments, it is a compound of formula (I), wherein p is 1-6. In some embodiments, it is a compound of formula (I), wherein p is 1-3. In some embodiments, it is a compound of formula (I), where p is 1 or 2. In some embodiments, it is a compound of formula (I), where p is 1. In some embodiments, it is a compound of formula (I), where p is 2. In some embodiments, it is a compound of formula (I), wherein p is 3. In some embodiments, it is a compound of formula (I), wherein p is 4. In some embodiments, it is a compound of formula (I), wherein p is 5. In some embodiments, it is a compound of formula (I), wherein p is 6. In some embodiments, it is a compound of formula (I), wherein p is 7. In some embodiments, it is a compound of formula (I), wherein p is 8. In some embodiments, it is a compound of formula (I), wherein p is 9.

In some embodiments, it is a compound of formula (I), wherein R ₁ is hydrogen. In some embodiments, a compound of formula (I), wherein, _{R 1} is _C 1 -C ₆ alkyl. In some embodiments, a compound of formula (I), wherein, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (I), wherein R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (I), wherein R ₁ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), where p is 1 and R ₁ is hydrogen. In some embodiments, it is a compound of formula (I), where p is 1 and R ₁ is C1-6 alkyl. In some embodiments, a compound of formula (I), wherein, p is is 1, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (I), where p is 1 and R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (I), where p is 1 and R ₁ is −CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (I), where p is 2 and R ₁ is hydrogen. In some embodiments, a compound of formula (I), wherein, p is 2, _{R 1} is _C 1 -C ₆ alkyl. In some embodiments, a compound of formula (I), wherein, p is 2, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (I), where p is 2 and R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (I), where p is 2 and R ₁ is −CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６は独立して、水素、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択され、Ｊは−ＮＨＣ（Ｏ）Ｒ_７または−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。

R ₆ is independently hydrogen, halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC. _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl , C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl, C _1- C ₉ heteroaryl, C ₆ -C _{10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl _sulfoxide, C 6 _{-C 10} aryl _sulfoxide, C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} Selected from aryl sulfones, J is -NHC (O) R ₇ or -C (O) OR ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N ( CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C ₃ −C ₈ cycloalkyl, C _{1 −} C ₆ fluoroalkyl, C _{1 −} C ₆ heteroalkyl, C _{1 −} C ₆ alkoxy, C _{1 −} C ₆ fluoroalkoxy, C _{2 −} C ₉ heterocyclo _alkyl, C 6 _{-C 10 aryl,} C 1 -C _{9 heteroaryl,} C 6 _{-C 10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl sulfoxide, _{C 6} - C ₁₀ aryl _{sulfoxide, C} 1 -C ₁ being optionally substituted with C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} 1 or more groups selected from arylsulfonic It is _{2 alkyl.}

In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６は独立して、水素、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択され、Ｊは−ＮＨＣ（Ｏ）Ｒ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is independently hydrogen, halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC. _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl , C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl, C _1- C ₉ heteroaryl, C ₆ -C _{10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl _sulfoxide, C 6 _{-C 10} aryl _sulfoxide, C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} Selected from aryl sulfones, J is -NHC (O) R ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1-) C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl, C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxide, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl , C _1- C ₉ Heteroaryl, C _6- C ₁₀ Aryloxy, C _1- C ₆ Alkthio, C _6- C ₁₀ Arylthio, C _1- C ₆ Alkyl Sulfoxide, C _6- C ₁₀ Aryl Sulfoxide, C _1- C _1- C ₁₂ alkyl optionally substituted with one or more groups selected from _{C 6} alkyl sulfone and C _6- C _{10 aryl sulfone.} In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６は独立して、水素、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択され、Ｊは−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。

R ₆ is independently hydrogen, halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC. _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl , C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl, C _1- C ₉ heteroaryl, C ₆ -C _{10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl _sulfoxide, C 6 _{-C 10} aryl _sulfoxide, C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} Selected from aryl sulfones, J is -C (O) OR ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1-) C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl, C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxide, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl , C _1- C ₉ Heteroaryl, C _6- C ₁₀ Aryloxy, C _1- C ₆ Alkthio, C _6- C ₁₀ Arylthio, C _1- C ₆ Alkyl Sulfoxide, C _6- C ₁₀ Aryl Sulfoxide, C _1- C _1- C ₁₂ alkyl optionally substituted with one or more groups selected from _{C 6} alkyl sulfone and C _6- C _{10 aryl sulfone.}

In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６はＣ_１−Ｃ_６アルコキシであり、Ｊは−ＮＨＣ（Ｏ）Ｒ_７または−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is C _1- C ₆ alkoxy, J is -NHC (O) R ₇ or -C (O) OR ₇ , and R ₇ is halogen, -CN, -NH ₂ ,- NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C) _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1-) C _{6 alkyl) 2,} C 1 -C _{6 alkyl,} C 3 -C _{8 cycloalkyl,} C 1 -C _{6 fluoroalkyl,} C 1 -C ₆ heteroalkyl _alkyl, C 1 -C _{6 alkoxy,} C 1 -C ₆ fluoro Alkoxy, C _2- C ₉ Heterocycloalkyl, C _6- C ₁₀ Aryl, C _1- C ₉ Heteroaryl, C _6- C ₁₀ Aryloxy, C _1- C ₆ Alkoxy, C _6- C ₁₀ Arylthio, C _{1 C 1-} C ₁₂ optionally substituted with one or more groups selected from -C ₆ alkyl sulfoxides, C _6- C ₁₀ aryl sulfoxides, C _1- C ₆ alkyl sulfones, and C _6- C _{10 aryl sulfones.} It is alkyl. In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６はＣ_１−Ｃ_６アルコキシであり、Ｊは−ＮＨＣ（Ｏ）Ｒ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is C _1- C ₆ alkoxy, J is -NHC (O) R ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N. (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl),- C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl, C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ hetero _cycloalkyl, C 6 _{-C 10 aryl,} C 1 -C _{9 heteroaryl,} C 6 _{-C 10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl sulfoxide, _{C 6} -C _1- C ₁₂ alkyl optionally substituted with one or more groups selected from _{C 10} aryl sulfoxide, C _1- C ₆ alkyl sulfone, and C _6- C _{10 aryl sulfone.} In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６はＣ_１−Ｃ_６アルコキシであり、Ｊは−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択される１つ以上の基で随意に置換されるＣ_１−Ｃ_１２アルキルである。

R ₆ is C _1- C ₆ alkoxy, J is -C (O) OR ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N. (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl),- C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl, C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ hetero _cycloalkyl, C 6 _{-C 10 aryl,} C 1 -C _{9 heteroaryl,} C 6 _{-C 10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl sulfoxide, _{C 6} -C _1- C ₁₂ alkyl optionally substituted with one or more groups selected from _{C 10} aryl sulfoxides, C _1- C ₆ alkyl sulfones, and C _6- C _{10 aryl sulfones.}

In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６は独立して、水素、ハロゲン、−ＣＮ、−ＮＨ_２、−ＮＨ（ＣＨ_３）、−Ｎ（ＣＨ_３）_２、−ＯＨ、−ＣＯ_２Ｈ、−Ｃ（Ｏ）ＯＣ_１−Ｃ_６アルキル、−Ｃ（Ｏ）ＮＨ_２、−Ｃ（Ｏ）ＮＨ（Ｃ_１−Ｃ_６アルキル）、−Ｃ（Ｏ）Ｎ（Ｃ_１−Ｃ_６アルキル）_２、−ＳＯ_２ＮＨ_２、−ＳＯ_２ＮＨ（Ｃ_１−Ｃ_６アルキル）、−ＳＯ_２Ｎ（Ｃ_１−Ｃ_６アルキル）_２、Ｃ_１−Ｃ_６アルキル、Ｃ_３−Ｃ_８シクロアルキル、Ｃ_１−Ｃ_６フルオロアルキル、Ｃ_１−Ｃ_６ヘテロアルキル、Ｃ_１−Ｃ_６アルコキシ、Ｃ_１−Ｃ_６フルオロアルコキシ、Ｃ_２−Ｃ_９ヘテロシクロアルキル、Ｃ_６−Ｃ_１０アリール、Ｃ_１−Ｃ_９ヘテロアリール、Ｃ_６−Ｃ_１０アリールオキシ、Ｃ_１−Ｃ_６アルキルチオ、Ｃ_６−Ｃ_１０アリールチオ、Ｃ_１−Ｃ_６アルキルスルホキシド、Ｃ_６−Ｃ_１０アリールスルホキシド、Ｃ_１−Ｃ_６アルキルスルホン、およびＣ_６−Ｃ_１０アリールスルホンから選択され、Ｊは−ＮＨＣ（Ｏ）Ｒ_７または−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は非置換のＣ_１−Ｃ_１２アルキルである。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is independently hydrogen, halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC. _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl , C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl, C _1- C ₉ heteroaryl, C ₆ -C ₁₀ Aryloxy, C _1- C ₆ Alkoxy, C _6- C ₁₀ Arylthio, C _1- C ₆ Aryl Sulfoxide, C _6- C _{10 Aryl Sulfoxide, C 1-} C ₆ Alkoxy Sulfone, and C _6- C ₁₀ Selected from aryl sulfones, J is -NHC (O) R ₇ or -C (O) OR ₇ , and R ₇ is an unsubstituted C _1- C ₁₂ alkyl. In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６はＣ_１−Ｃ_６アルコキシであり、Ｊは−ＮＨＣ（Ｏ）Ｒ_７または−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は非置換のＣ_１−Ｃ_１２アルキルである。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is C _1- C ₆ alkoxy, J is -NHC (O) R ₇ or -C (O) OR ₇ , and R ₇ is an unsubstituted C _1- C ₁₂ alkyl. .. In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６はＣ_１−Ｃ_６アルコキシであり、Ｊは−ＮＨＣ（Ｏ）Ｒ_７であり、ならびにＲ_７は非置換のＣ_１−Ｃ_１２アルキルである。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

R ₆ is C _1- C ₆ alkoxy, J is -NHC (O) R ₇ , and R ₇ is an unsubstituted C _1- C ₁₂ alkyl. In some embodiments, it is a compound of formula (I), wherein Y is

であり、Ｒ_６はＣ_１−Ｃ_６アルコキシであり、Ｊは−Ｃ（Ｏ）ＯＲ_７であり、ならびにＲ_７は非置換のＣ_１−Ｃ_１２アルキルである。

R ₆ is C _1- C ₆ alkoxy, J is -C (O) OR ₇ , and R ₇ is an unsubstituted C _1- C ₁₂ alkyl.

In some embodiments, it is a compound of formula (I), wherein Y is

である。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

Is. In some embodiments, it is a compound of formula (I), wherein Y is

である。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

Is. In some embodiments, it is a compound of formula (I), wherein Y is

である。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

Is. In some embodiments, it is a compound of formula (I), wherein Y is

である。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

Is. In some embodiments, it is a compound of formula (I), wherein Y is

である。いくつかの実施形態では、式（Ｉ）の化合物であって、式中、Ｙは

Is. In some embodiments, it is a compound of formula (I), wherein Y is

である。

Is.

In another embodiment, the present specification describes a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a hydrate.

式中、
Ｒ_１は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_２は、−（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）（ＣＨ_２）_ｍＯ（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｏ（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｎ（Ｒ_４）（ＣＨ_２ＣＨ_２Ｏ）_ｎＲ_３、−Ｃ（Ｏ）Ｒ_５、−Ｃ（Ｏ）ＯＲ_５、または−Ｃ（Ｏ）Ｎ（Ｒ_４）（Ｒ_５）であり、
Ｒ_３は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_４は水素またはＣ_１−Ｃ_６アルキルであり、
Ｒ_５はＣ_１−Ｃ_５０アルキルであり、
ｍは１〜１０であり、
ｎは１〜５０であり、ならびに
ｐは１〜９である。

During the ceremony
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is-(CH _{2 CH 2} O) _n R ₃ , -C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) ) _N R ₃ , -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ , -C (O) R ₅ , -C (O) OR ₅ , or -C (O) N ( R ₄ ) (R ₅ ),
R ₃ is hydrogen or C _1- C ₆ alkyl,
R ₄ is hydrogen or _C 1 -C ₆ alkyl,
R ₅ is C _1- C ₅₀ alkyl and is
m is 1 to 10
n is 1 to 50, and p is 1 to 9.

In some embodiments, it is a compound of formula (II), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ , −C (O) (CH ₂ ) _m O (CH ₂ CH). ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) _n R ₃ , or -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ .

In some embodiments, it is a compound of formula (II), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₃ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is − CH ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is − (CH ₂ CH ₂ O) _n R ₃ and R ₃ is − CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. It is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. It is C _1- C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. It is a C _1- C ₃ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. -CH ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is. -CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₆ It is alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C _{1 −} C ₃ It is alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is -C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is -CH ₃ . .. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −CH ₂ CH ₃ Is.

In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. Is. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. in and, _{R 4} is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is hydrogen. in and, _{R 4} is _C 1 -C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₆ alkyl and R ₄ is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₆ alkyl and R ₄ is C _1- C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₃ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₃ alkyl and R ₄ is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is C. _{It is 1-} C ₃ alkyl and R ₄ is C _1- C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. It is CH _3. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. CH ₃ and R ₄ are hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. is CH _{3, R 4} is _C 1 -C ₆ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. CH ₂ CH ₃ In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. CH ₂ CH ₃ and R ₄ is hydrogen. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ and R ₃ is −. a CH ₂ CH _{3, R 4} is _C 1 -C ₆ alkyl.

In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ . In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₄₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is —C (O) R ₅ and R ₅ is C ₁ −C ₄₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₃₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₃₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₂₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₂₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₁₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) R ₅ and R ₅ is C ₁ −C ₁₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is —C (O) R ₅ and R ₅ is C ₁ −C ₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is -C (O) R ₅ and R ₅ is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), wherein R ₂ is -C (O) R ₅ and R ₅ is -CH ₃ .

In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ . In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₄₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₄₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is -C (O) OR ₅ and R ₅ is C _1- C ₃₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₃₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₂₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₂₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is —C (O) OR ₅ and R ₅ is C ₁ −C ₁₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is C ₁ −C ₁₀ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is -C (O) OR ₅ and R ₅ is C _1- C ₅ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₂ is -C (O) OR ₅ and R ₅ is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) OR ₅ and R ₅ is −CH ₃ .

In some embodiments, it is a compound of formula (II), wherein R ₂ is −C (O) N (R ₄ ) (R ₅ ). In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. a C ₁ -C ₄₅ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. a C ₁ -C ₄₀ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. a C ₁ -C ₃₅ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₃₀ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₂₅ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₂₀ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₁₅ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is C _1- C ₁₀ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. It is a C _1- C ₅ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is −C (O) N (R ₄ ) (R ₅ ), R ₄ is H and R ₅ is. -CH ₃ .

In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 45} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 40} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 35} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 30} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 25} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 20} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 15} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 _{-C 10} alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. There, _{R 5} is _C 1 -C ₅ alkyl. In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. Yes, R ₅ is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ) and R ₄ is C _1- C ₆ alkyl. Yes, R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ), R ₄ is -CH ₃ and R. ₅ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), in which R ₂ is -C (O) N (R ₄ ) (R ₅ ), R ₄ is -CH ₃ and R. ₅ is −CH ₃ .

In some embodiments, it is a compound of formula (II), wherein m is 1-5. In some embodiments, it is a compound of formula (II), wherein m is 2-10. In some embodiments, it is a compound of formula (II), wherein m is 4-10. In some embodiments, it is a compound of formula (II), wherein m is 2-8. In some embodiments, it is a compound of formula (II), wherein m is 2-6. In some embodiments, it is a compound of formula (II), wherein m is 2-4. In some embodiments, it is a compound of formula (II), wherein m is 1. In some embodiments, it is a compound of formula (II), wherein m is 2. In some embodiments, it is a compound of formula (II), wherein m is 3. In some embodiments, it is a compound of formula (II), wherein m is 4. In some embodiments, it is a compound of formula (II), wherein m is 5. In some embodiments, it is a compound of formula (II), wherein m is 6. In some embodiments, it is a compound of formula (II), wherein m is 7. In some embodiments, it is a compound of formula (II), wherein m is 8. In some embodiments, it is a compound of formula (II), wherein m is 9. In some embodiments, it is a compound of formula (II), wherein m is 10.

In some embodiments, it is a compound of formula (II), wherein n is 1-45. In some embodiments, it is a compound of formula (II), wherein n is 1-40. In some embodiments, it is a compound of formula (II), wherein n is 1-35. In some embodiments, it is a compound of formula (II), wherein n is 1-30. In some embodiments, it is a compound of formula (II), wherein n is 1-25. In some embodiments, it is a compound of formula (II), wherein n is 1-20. In some embodiments, it is a compound of formula (II), wherein n is 2-20. In some embodiments, it is a compound of formula (II), wherein n is 2-16. In some embodiments, it is a compound of formula (II), wherein n is 2-12. In some embodiments, it is a compound of formula (II), wherein n is 3-12. In some embodiments, it is a compound of formula (II), wherein n is 2-10. In some embodiments, it is a compound of formula (II), wherein n is 4-10. In some embodiments, it is a compound of formula (II), wherein n is 3-12. In some embodiments, it is a compound of formula (II), where n is 1. In some embodiments, it is a compound of formula (II), where n is 2. In some embodiments, it is a compound of formula (II), where n is 3. In some embodiments, it is a compound of formula (II), where n is 4. In some embodiments, it is a compound of formula (II), where n is 5. In some embodiments, it is a compound of formula (II), where n is 6. In some embodiments, it is a compound of formula (II), where n is 7. In some embodiments, it is a compound of formula (II), where n is 8. In some embodiments, it is a compound of formula (II), where n is 9. In some embodiments, it is a compound of formula (II), where n is 10. In some embodiments, it is a compound of formula (II), where n is 11. In some embodiments, it is a compound of formula (II), wherein n is 12. In some embodiments, it is a compound of formula (II), wherein n is 13. In some embodiments, it is a compound of formula (II), where n is 14. In some embodiments, it is a compound of formula (II), where n is 15. In some embodiments, it is a compound of formula (II), where n is 16.

In some embodiments, it is a compound of formula (II), wherein p is 1-6. In some embodiments, it is a compound of formula (II), wherein p is 1-3. In some embodiments, it is a compound of formula (II), where p is 1 or 2. In some embodiments, it is a compound of formula (II), where p is 1. In some embodiments, it is a compound of formula (II), wherein p is 2. In some embodiments, it is a compound of formula (II), wherein p is 3. In some embodiments, it is a compound of formula (II), wherein p is 4. In some embodiments, it is a compound of formula (II), wherein p is 5. In some embodiments, it is a compound of formula (II), wherein p is 6. In some embodiments, it is a compound of formula (II), wherein p is 7. In some embodiments, it is a compound of formula (II), wherein p is 8. In some embodiments, it is a compound of formula (II), wherein p is 9.

In some embodiments, it is a compound of formula (II), wherein R ₁ is hydrogen. In some embodiments, a compound of Formula (II), wherein, _{R 1} is _C 1 -C ₆ alkyl. In some embodiments, a compound of Formula (II), wherein, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (II), wherein R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (II), wherein R ₁ is −CH ₂ CH ₃ .

In some embodiments, it is a compound of formula (II), where p is 1 and R ₁ is hydrogen. In some embodiments, it is a compound of formula (II), where p is 1 and R ₁ is C1-6 alkyl. In some embodiments, a compound of Formula (II), wherein, p is is 1, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (II), where p is 1 and R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (II), where p is 1 and R ₁ is −CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), where p is 2 and R ₁ is hydrogen. In some embodiments, it is a compound of formula (II), where p is 2 and R ₁ is C1-6 alkyl. In some embodiments, a compound of Formula (II), wherein, p is 2, _{R 1} is _C 1 -C ₃ alkyl. In some embodiments, it is a compound of formula (II), where p is 2 and R ₁ is −CH ₃ . In some embodiments, it is a compound of formula (II), in which p is 2 and R ₁ is −CH ₂ CH ₃ .

Provided herein are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 1 to 10
n is 1 to 30, and p is 1 to 9.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 1-5,
n is 2 to 20 and p is 1 to 5.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 1-5,
n is 2-12, and p is 1-5.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 1 or 2
n is 2-12, and p is 1 or 2.

Provided herein are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 2
n is 2-12, and p is 1.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 2
n is 3-12, and p is 1.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is C _1- C ₆ alkyl and is
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is C _1- C ₆ alkyl and is
m is 1-5,
n is 3-12, and p is 1-5.

Provided herein are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein
R ₁ is C _1- C ₆ alkyl and is
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is C _1- C ₆ alkyl and is
m is 2
n is 3-12, and p is 1.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 2
n is 3 and p is 1.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 2
n is 6 and p is 1.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 2
n is 9 and p is 1.

The present specification provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of the formula (II) is used.
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ and
R ₃ is hydrogen or C _1- C ₆ alkyl,
m is 2
n is 12 and p is 1.

In another embodiment, there is a compound selected from the following, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, there is a compound selected from the following, or a pharmaceutically acceptable salt or solvate thereof.

Synthesis of Compounds In some embodiments, synthesis of the compounds described herein is accomplished by means described in the chemical literature, by the methods described herein, or by a combination thereof. Will be done. In addition, the solvents, temperatures, and other reaction conditions provided herein are subject to change.

In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or, but not limited to, Sigma-Aldrich Corp. , Obtained from commercial sources such as Fisher Scientific (Fisher Scientifics) and Across Organics.

In a further embodiment, the compounds described herein, and other related compounds having various substituents, are the techniques and materials described herein, as well as, for example, those described in the following literature. Synthesized using techniques and materials recognized in the art: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed. , (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed. , Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed. , (Wiley 1999) (all of these references are cited by reference to their disclosure). The general method for the preparation of compounds as disclosed herein may be derived from a reaction, which introduces various moieties found in the chemical formulas as provided herein. May be modified with appropriate reagents and conditions.

Further Forms of Compounds The compounds described herein may optionally be present in the form of diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include the forms of diastereomers, enantiomers, and epimers, as well as all suitable mixtures thereof. Separation of stereoisomers can be performed by chromatographic or diastereomeric formation and recrystallization or chromatographic separation, or any combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers". , Racemates and Resolutions ”, John Wiley And Sons, Inc., Inc., 1981; this document is cited by reference for disclosure). Stereoisomers may be obtained by stereoselective synthesis.

In some situations, the compound may exist as a tautomer. All tautomers are included within the formulas described herein.

The methods and compositions described herein include the use of amorphous as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds with the same type of activity are within the scope of the present disclosure. In addition, the compounds described herein can exist in solvated form, including non-solvate forms as well as pharmaceutically acceptable solvents such as water and ethanol. Solvation forms of the compounds presented herein are also considered as disclosed herein.

The compounds of formula (I) or (II) described herein, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, or hydrates, are prodrugs of TRPV1 agonists. .. "Prodrug" refers to a drug that is converted to the parent drug in vivo. The compounds of formula (I) or (II) described herein, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, or hydrates, are novel water solubility of TRPV1 agonists. It targets prodrugs and their synthesis and usage methods. In addition to specifically identified compounds, these derivatives can be chemicals that revert to the active parent compound when exposed to physiological conditions. Such derivatives have significantly higher hydrophilicity / water solubility than their parent drug and therefore can be suitably incorporated into commonly used aqueous formulations. Further described herein are methods of increasing the water solubility of capsaicin, its analogs, and other TRPV1 agonists by modifying the chemical structure of a prodrug with a hydrophilic moiety. In the embodiments described herein, the introduction of a basic moiety that can be protonated under acidic conditions increases the solubility of the TRPV1 agonist prodrug. The prodrugs described herein are designed to release the parent drug at a well-defined rate after the structural derivative has been delivered to the body and / or exposed to certain physiological conditions. NS.

The compounds described herein are either isotopically (eg, by radioisotope) labeled or of a chromophore or fluorescent moiety, bioluminescent label, light-activated label or chemiluminescent label. It may be labeled by other means including, but not limited to, use.

The compounds described herein include isotope-labeled compounds in which one or more atoms are replaced by an atom having an atomic mass or mass number that is different from the atom mass or mass number normally found in nature. Except for the fact that it is, it is the same as that listed in the various formulas and structures presented herein. Examples of isotopes that can be incorporated into this compound are hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine isotopes, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, respectively. Can be mentioned. Isotope-labeled compounds described herein, such as compounds incorporating radioisotopes such as 3H and 14C, are useful in drug and / or substrate tissue distribution assays. In addition, substitution with deuterium or isotopes such as 2H can provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosing conditions.

The compounds described herein are formed as pharmaceutically acceptable salts and / or may be used as pharmaceutically acceptable salts. The types of pharmaceutically acceptable salts include, but are not limited to, pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphate, or, for example acetic acid, propionic acid, Hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartrate acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) ) Saccharic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalinsulfonic acid, 4-methyl Bicyclo- [2.2.2] octa-2-en-1-carboxylic acid, glucopeptonic acid, 4,4'-methylenebis- (3-hydroxy-2-en-1-carboxylic acid), 3-phenylpull Free of compounds in organic acids such as pionic acid, trimethylacetic acid, tertiarybutylacetic acid, laurylsulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid and valproic acid. Examples thereof include acid addition salts formed by reacting the base morphology. In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine and lysine.

It should be understood that references to pharmaceutically acceptable salts include their solvent-added forms or crystals, specifically solvent compounds or polymorphs. Solvates may contain either stoichiometric or non-stoichiometric solvents and may be formed during the process of crystallization with a pharmaceutically acceptable solvent such as water or ethanol. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein. In addition, the compounds provided herein can exist in solvated form as well as in non-solvated form. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds and methods provided herein.

In some embodiments, the compounds described herein are compounds of formula (I) or (II), including but not limited to amorphous, pulverized, and nanoparticulate shapes. exist. In addition, the compounds described herein contain crystalline forms also known as polymorphs. Polymorphs contain different crystal packed arrangements of the same elemental composition of the compound. Polymorphs usually have various X-ray diffraction patterns, melting points, densities, hardnesses, crystal shapes, optical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, storage temperature, etc. may cause the dominant single crystal morphology.

Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates includes, but is not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor adsorption, and microscopic observation. May be performed using. Thermal analysis methods are intended for thermochemical decomposition or thermophysical treatments including, but not limited to, polymorphic transitions, such methods for analyzing relationships between polymorphs. It is used to determine the weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include, but are limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric analysis / infrared analysis (TG / IR). Not done. Examples of the X-ray diffractometry include, but are not limited to, a single crystal, a powder diffractometer, and a synchrotron source. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, NMR (liquid and solid state). Various microscopy techniques include polarization microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gas or steam atmosphere), IR. Examples thereof include, but are not limited to, a microscope observation method and a Raman microscope observation method.

Throughout the specification, groups and substituents thereof to provide stable moieties and compounds can be selected.

Use of protecting groups (PG)
In the described reactions, if reactive functional groups such as hydroxy, amino, imino, thio, carboxy are desired in the final product to avoid undesired participation in the reaction. It may be necessary to protect these. Protecting groups are used to block some or all of the reaction moieties and prevent such groups from engaging in chemical reactions until the protecting groups are removed. It is preferred that each protecting group can be removed by different means. Protecting groups that are cleaved under totally different reaction conditions meet the requirements for differential removal.

Protecting groups can be removed by acids, bases, reducing conditions (eg, hydrocracking, etc.), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetyl, and t-butyldimethylsilyl are acid-degradable and in the presence of Cbz groups that can be removed by hydrocracking and amino groups that are protected by the basic-degradable Fmoc group. It may be used to protect each reaction moiety of carboxy and hydroxy. The reaction moiety between the carboxylic acid and the hydroxy is under an acid unstable group such as t-butyl carbamate, or in the presence of an acid-stable and base-stable but hydrolyzable carbamate-blocked amine. It may be blocked by a base unstable group such as, but not limited to, methyl, ethyl, and acetyl.

The reaction moiety between the carboxylic acid and the hydroxy may be further blocked by a hydrolyzable protecting group such as a benzyl group, while the amine group capable of hydrogen bonding with the acid is a basic degradable group such as Fmoc. It may be blocked. Carboxylic acid reaction moieties are protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or oxidatively removable protection such as 2,4-dimethoxybenzyl. It may be blocked by a group, but the coexisting amino group may be blocked by a fluoride-unstable silylcarbamate.

Allyl blocking groups are useful in the presence of acid protectors and base protectors because the acid protectors are stable and can be continuously removed by metal or pi-acid catalysts. For example, a carboxylic acid blocked by an allyl can be deprotected by a Pd0-catalyzed reaction in the presence of an acid-labile t-butyl carbamate or a base-labile amine acetate protecting group. Another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional groups are available for the reaction.

Generally, the blocking group / protecting group may be selected from the following.

In addition to other protecting groups, a detailed description of the techniques applicable to the generation and removal of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed. , John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Threeme Verlag, New York, NY, 1994, which are incorporated herein by reference.

Disease, Disorder, or Disease In another aspect, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or pharmaceutically acceptable thereof. It comprises administering to said subject a possible salt, a pharmaceutically acceptable solvate, or a hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with postoperative pain, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, and the pain is associated with chronic postoperative pain. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, said pain associated with neuropathic pain. In some embodiments, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvent or hydrate, and the pain is associated with postherpetic neuralgia. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with diabetic neuropathy, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with HIV-related neuropathy, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, said pain is associated with complex regional pain syndrome. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with cancer, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, said pain is associated with chemotherapeutic treatment of the cancer. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, said pain is associated with nerve injury. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with genital pain, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with trauma, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with surgery, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, the pain being associated with chronic musculoskeletal pain. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with back pain, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, and the pain is associated with osteoarthritis or rheumatoid arthritis. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with osteoarthritis, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with rheumatoid arthritis, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. It comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, the pain associated with bursitis, tendinitis, lateral epicondylitis. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with intercarpal syndrome, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with Morton's neuroma, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with compartment syndrome, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with spinal cord injury, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, and the pain is associated after cleavage. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, the pain being associated with illusionary limb pain. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, said pain is associated with end-stage cancer pain. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, and the pain is associated with peripheral neuropathy. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with visceral pain, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with interstitial cystitis, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain is associated with overactive bladder, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The pain comprises administering to the subject a pharmaceutically acceptable solvate or hydrate, said pain is associated with radiculopathy. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. It comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, the pain associated with rib and long bone crushing.

In some embodiments, a method of treating a subject's psoriasis, pruritus, itch, or cancer, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a compound thereof. It comprises the step of administering to said subject a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a hydrate. In some embodiments, a method of treating psoriasis in a subject, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. It comprises the step of administering to said subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating pruritus in a subject, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. , Includes the step of administering to said subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating itching of a subject, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. It comprises the step of administering to said subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's cancer, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. It comprises the step of administering to said subject a pharmaceutically acceptable solvate or hydrate.

In some embodiments, a method of treating a subject's pain, wherein the method is a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The compound is administered topically, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The compound comprises the step of administering to the subject a pharmaceutically acceptable solvate or hydrate, the compound being administered skin. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The compound is transdermally administered, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate. In some embodiments, a method of treating a subject's pain, wherein the method comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. The compound is administered systemically, comprising the step of administering to the subject a pharmaceutically acceptable solvate or hydrate.

Specific Terms Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood to which the invention-specific matters belong. If there are multiple definitions of the terms herein, the definitions in this chapter will prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences cited herein (eg, sequences available in databases such as GenBank) are cited by reference. When referring to identifiers or addresses such as URLs, such identifiers are subject to change, and certain information on the Internet may appear or disappear, but equivalent information may be found by searching the Internet. Understood. References to these support the availability and public dissemination of such information.

It should be understood that the general description described above and the detailed description below are merely typical and exemplary and are not limited to the invention-specific matters within the scope of the claims. In this application, the use of the singular includes the plural unless otherwise stated. It is noted that, within the scope of this specification and the accompanying claims, the singular forms "a", "an", and "the" include multiple referents unless otherwise explicitly stated. sea bream. In this application, the use of "or" means "and / or" unless otherwise stated. Further, the use of the term "include" is not limited, as is the case with other forms such as "include", "includes", "included" and the like.

The chapter headings used herein are for structural purposes only and should not be construed as limiting the invention-specific matters described.

The definition of standard chemical terms is Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. It can also be found in references including, but not limited to, A (2000) and B (2001), Plenum Press, New York. Unless otherwise specified, conventional methods are mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology.

Unless a specific definition is given, the nomenclatures adopted in connection with analytical chemistry, synthetic organic chemistry, and medicinal chemistry and medicinal chemistry described herein, as well as the procedures and techniques for testing them, are such techniques. It is recognized in the field. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation, and delivery, as well as patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (eg, electroporation, lipofection). Reaction and purification techniques can be performed, for example, using kits from the manufacturer's specifications, or as commonly performed in the art, or as described herein. The techniques and procedures described above can be performed in the conventional manner as a whole, as well as as described in the various general and more specific references cited and considered throughout this specification. ..

It should be understood that the methods and compositions described herein are not limited to the particular methods, protocols, cell lines, constructs, and reagents described herein and may vary as required. .. The terms used herein are intended to describe only certain embodiments and may not be intended to limit the scope of the methods, compounds, or compositions described herein. I want you to understand.

As used herein, C1-Cx is C1-C2, C1-C3. .. .. Includes C1-Cx. C1-Cx refers to the number of carbon atoms that make up the moiety it specifies (other than any substituent).

The "alkyl" group refers to an aliphatic hydrocarbon group, where the carbon hybridized with sp3 of the alkyl residue is attached to the rest of the molecule by a single bond. Alkyl groups may or may not contain unsaturated units. The alkyl moiety may be a "saturated alkyl" group, which means that the alkyl moiety does not contain units of unsaturated (ie, carbon-carbon double or carbon-carbon triple bonds). The alkyl group may further be an "unsaturated alkyl" moiety, which means that the alkyl group comprises at least one unsaturated unit. The alkyl moiety may be branched, straight or cyclic, whether saturated or unsaturated.

An "alkyl" group may have 1 to 6 carbon atoms (whenever an alkyl appears herein, a range of numbers such as "1-6" can be an integer within a given range. For example, "1 to 6 carbon atoms" means that the alkyl group may consist of up to 6 carbon atoms such as 1 carbon atom, 2 carbon atoms, and 3 carbon atoms. However, this definition also includes the appearance of the term "alkyl" if no range of numbers is specified). Alkyl group of the compounds described herein may be designated as "C ₁ -C ₆ alkyl" or similar names. As just one example, "C _1- C ₆ alkyl" means that there are 1 to 6 carbon atoms in the alkyl chain, that is, the alkyl chain is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso. A group consisting of -butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propene-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Indicates that it is selected from. The alkyl group may be substituted or unsubstituted. The alkyl group may be a monoradical or a diradical (ie, an alkylene group) depending on the structure.

"Alkoxy" refers to the "-O-alkyl" group, where alkyl is as defined herein.

The term "alkenyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, the alkenyl group starts at atom-C (R) = CR2, where R refers to the rest of the alkenyl group, which may be the same or different. Non-limiting examples of alkenyl _{groups, -CH = CH2, -C (CH} 3) = CH2, -CH = CHCH3, -CH = C (CH3) 2, include -C (CH3) = CHCH3. The alkenyl moiety may be branched, linear, or cyclic (in all cases, identified as a "cycloalkenyl" group). The alkenyl group may have 2 to 6 carbons. The alkenyl group may be substituted or unsubstituted. The alkenyl group may be a monoradical or a diradical (ie, an alkenylene group) depending on the structure.

The term "alkynyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, the alkynyl group starts with the atom -C≡CR, where R refers to the rest of the alkynyl group. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH ₃ , -C≡CCH ₂ CH ₃ , -C≡CCH ₂ CH ₂ CH ₃ . The "R" portion of the alkynyl moiety may be branched, straight or cyclic. The alkynyl group may have 2 to 6 carbons. The alkynyl group may be substituted or unsubstituted. The alkynyl group may be a monoradical or a diradical (that is, an alkynylene group) depending on the structure.

"Amino" refers to -NH2 groups.

The term "alkylamine" or "alkylamino" refers to the -N (alkyl) xHy group, where alkyl is as defined herein, where x and y are groups x = 1, y = 1, And x = 2, y = 0. When x = 2, the alkyl groups can optionally form a cyclic ring system together with the nitrogen to which they are attached. "Dialkylamino" refers to two -N (alkyl) groups, where alkyl is as defined herein.

The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n + 2π electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or 9 or more atoms. Aromatic compounds can be replaced at will. The term "aromatic" includes both aryl groups (eg, phenyl, naphthalenyl) and heteroaryl groups (eg, pyridinyl, quinolinyl).

As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings can be formed of 5, 6, 7, 8, 9, or 9 or more carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. The aryl group may be a monoradical or a diradical (ie, an arylene group) depending on the structure.

As used herein, the term "acyl" refers to a group containing a carbonyl moiety, which is attached via a carbonyl carbon atom. The carbonyl carbon atom is attached to yet another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, heterocycloalkyl, heteroaryl group, and the like.

"Carboxy" refers to _{-CO 2 H.} In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere", which is a functional group or functional group exhibiting similar physical and / or chemical properties as the carboxylic acid moiety. Refers to the part. Carboxylic acid bioisostars have similar biological properties as carboxylic acid groups. A compound having a carboxylic acid moiety can have a carboxylic acid moiety exchanged for a carboxylic acid bioisostar and has similar physical and / or biological properties when compared to a carboxylic acid containing compound. For example, in one embodiment, the carboxylic acid bioisostar is ionized in about the same range as the carboxylic acid group at physiological pH. Examples of carboxylic acid bioisostars include, but are not limited to:

The term "cycloalkyl" refers to monocyclic or polycyclic non-aromatic radicals, where each of the atoms forming the ring (ie, the skeletal atom) is a carbon atom. Cycloalkyl may be saturated or partially unsaturated. Cycloalkyl may be condensed with an aromatic ring (in which case the cycloalkyl is bonded via a non-aromatic ring carbon atom). Cycloalkyl groups include groups with 3-10 ring atoms. Examples of cycloalkyl groups include, but are not limited to, the following:

The term "heteroaryl", or alternative "heteroaromatic", represents an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroaryl groups may or may not be condensed. Examples of heteroaryl groups include the following:

The "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. Radicals may be condensed with aryl or heteroaryl. The heterocycloalkyl group is also referred to as a non-aromatic heterocycle, and examples thereof include the following.

用語「ヘテロ脂環式」はまた、単糖類、二糖類、オリゴ糖類を含むがこれらに限定されない炭水化物の環形すべてを含む。他に明記されない限り、ヘテロシクロアルキルは環に２〜１０個の炭素を有する。ヘテロシクロアルキル中の炭素原子の数を指すとき、ヘテロシクロアルキル中の炭素原子の数は、ヘテロシクロアルキル（すなわちヘテロシクロアルキル環の骨格原子）を構築する原子（ヘテロ原子を含む）の総数と同じでないことが理解される。

The term "heteroalicyclic" also includes all carbohydrate rings including, but not limited to, monosaccharides, disaccharides, oligosaccharides. Unless otherwise stated, heterocycloalkyl has 2-10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (ie, the skeletal atoms of the heterocycloalkyl ring). It is understood that they are not the same.

The term "halo" or alternative "halogen" means fluoro, chloro, bromo, and iodine.

The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogens. The halogens may be the same or different. Non-limiting examples of haloalkyl include -CH ₂ Cl, -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF (CH ₃ ) ₂ . Non-limiting examples of haloalkoxy include -OCH ₂ Cl, -OCF ₃ , -OCHF ₂ , -OCH ₂ CF ₃ , -OCF ₂ CF ₃ , -OCF (CH ₃ ) ₂ .

The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups substituted with one or more fluorine atoms, respectively. Non-limiting examples of fluoroalkyl are -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , -CF (CH ₃ ) ₃ And so on. Non-limiting examples of fluoroalkoxy groups are -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCF ₂ CF ₃ , -OCF ₂ CF ₂ CF ₃ , -OCF (CH ₃ ). _{2 and the} like.

The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal chain atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or a combination thereof. Heteroatoms may be located at any internal position of the heteroalkyl group. As an example, -CH _2- O-CH ₃ , -CH _{2 -CH 2-} O-CH ₃ , -CH _2- NH-CH ₃ , -CH _{2 -CH 2-} NH-CH ₃ , -CH _2- N (CH ₃ ) -CH ₃ , -CH _{2 -CH 2-} NH-CH ₃ , -CH _{2 -CH 2-} N (CH ₃ ) -CH ₃ , -CH _2- S-CH _{2 -CH 3} , -CH _2- CH ₂ , -S (O) -CH ₃ , -CH _2- CH _2- S (O) _2- CH ₃ , -CH _2- NH-OCH ₃ , -CH ₂ O-Si (CH ₃ ) ₃ , -CH _2- CH = N-OCH ₃ , and -CH = CH-N (CH ₃ ) -CH ₃ . In addition, a maximum of two heteroatoms may be continuous, and examples thereof include -CH _2- NH-OCH ₃ and -CH _2- O-Si (CH ₃ ) ₃ . In addition to the number of heteroatoms, the "heteroalkyl" may have 1 to 6 carbon atoms.

The term "single bond" or "single bond" is used between two atoms or two parts when an atom linked in a single bond is considered to be part of a larger partial structure. Refers to a chemical bond.

The term "part" refers to a particular region or functional group of a molecule. Chemical moieties are often perceived as chemicals embedded in or attached to a molecule.

As used herein, the substituent "R" that appears alone and has no indication of the number is alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded via ring carbon). ), And a substituent selected from heterocycloalkyl.

The term "optionally substituted" or "substituted" refers to groups such as alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, Aryl Sulfoxide, Alkyl Sulfoxide, Aryl Sulfonate, -CN, Alkin, C _1- C ₆ Alkyl Alkin, Halo, Acrylic, Acyloxy, -CO ₂ H, -CO ₂ -alkyl, Nitro, Halo Alkyl, Fluoroalkyl, Fluoroalkoxy, and. Aminos containing mono- and di-substituted amino groups (eg, -NH ₂ , -NHR, -N (R) ₂ ), as well as one or more additional groups individually and independently selected from these protected derivatives. It means that it may be replaced with. In some embodiments, the optional substituents are independently halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -CO. ₂ Alkoxy, -C (= O) NH ₂ , -C (= O) NH (alkyl), -C (= O) N (alkyl) ₂ , -S (= O) ₂ NH ₂ , -S (= O) ) ₂ NH (alkyl), -S (= O) ₂ N (alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, It is selected from arylthios, alkylsulfoxides, arylsulfoxides, alkylsulphones, and arylsulfones. In some embodiments, the optional substituents are independent, halogen, -CN, -NH ₂ , -OH, -NH (CH ₃ ), -N (CH ₃ ) ₂ , -CH ₃ , -CH _2. It is selected from CH ₃ , -CF ₃ , -OCH ₃ , and -OCF _3. In some embodiments, the substituted group is substituted with one or two of the aforementioned groups. In some embodiments, any substituent on the aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atom excluding aromatic carbon atoms) comprises oxo (= O). ..

"Counterion" refers to an ion with a seed of ion to maintain electrical neutrality. Examples of counterions include Cl ⁻ , Br ⁻ , I ⁻ , and CF ₃ CO ₂ ⁻ .

The methods and formulations described herein are of the same type, as well as pharmaceutically acceptable salts of compounds having a crystalline form (also known as polymorphs) or structures of formula (I) or (II). Includes the use of active metabolites of these compounds with the activity of. Depending on the circumstances, the compound may exist as a tautomer. All tautomers are included within the scope of the compounds described herein. In addition, the compounds described herein can exist not only in non-solvate forms, but also in solvated forms containing pharmaceutically acceptable solvents such as water and ethanol. Solvation forms of the compounds presented herein are also considered as disclosed herein.

The terms "kit" and "product" are used as synonyms.

The term "subject" or "patient" includes mammalian and non-mammalian animals. Examples of mammals include members of the following mammalian classes: humans, non-human primates such as chimpanzees, and other apes and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; rabbits, dogs, Domestic animals such as cats; experimental animals including, but not limited to, rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The terms "treat," "treat," or "treat," as used herein, alleviate, alleviate, or ameliorate a disease or disease, or prevent additional symptoms. , Ameliorating or preventing the underlying cause of the disease, inhibiting the disease or disease, eg, slowing the progression of the disease or disease, relieving the disease or disease, causing the disease or disease regression, disease or It involves relieving the condition caused by the disease or prophylactically and / or therapeutically stopping the disease or symptoms of the disease.

As used herein, amelioration of a particular disease, disorder, or symptom of a particular disease by administration of a particular compound or pharmaceutical composition is due to or associated with the administration of the compound or composition. Refers to any reduction in severity, delayed onset, slowed progression, or permanent or temporary and permanent or transient shortening of duration.

The term "regulating", as used herein, alters the activity of a target protein, including, by way of example, inhibiting the activity of the target, or limiting or reducing the activity of the target. Therefore, it means interacting with the target protein directly or indirectly.

As used herein, the term "modulator" refers to a compound that modifies the activity of a target. Modulators, for example, can cause an increase or decrease in the scale of a particular activity of a target compared to the scale of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor, which reduces the scale of activity of one or more of the targets. In certain embodiments, the inhibitor completely prevents the activity of one or more of the targets.

As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effect on the overall health of the subject being treated. do.

"Pharmaceutically acceptable" as used herein refers to a material, such as a carrier or diluent, that is relatively non-toxic without suppressing the biological activity or properties of the compound. This material is administered to an individual without causing undesired biological effects or adversely interacting with any of the components of the composition in which it is contained.

As used herein, the term "pharmaceutical formulation" means a product produced by mixing or blending more than one active ingredient, including both fixed and non-fixed formulations of the active moiety. The term "fixed formulation" refers to the co-administration of one active ingredient, eg, a compound of formula (I) or (II) and an adjunct, to a patient in the form of a single substance or dose. The term "non-fixed formulation" means that one active ingredient, eg, a compound of formula (I) or (II) and an adjunct, are simultaneously, parallel or consecutively separate entities without the intervention of a particular time limit. Representing being administered to a patient, such administration results in an effective level of the two compounds on the patient's body. The latter is also applied to cocktail therapy, eg administration of three or more active ingredients.

The term "pharmaceutical composition" is a compound of formula (I) or (II) described herein and a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. Represents a mixture with other chemical components such as agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques for administering compounds exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

The term "capsaicinoid or capsaicin analog" refers to (E) -capsaicin, resiniferatoxin, AM-404 (N- (4-hydroxyphenyl) -5Z, 8Z, 11Z, 14Z- Eikosatetraeneamide), anandamide, arvanil, 6'-iodresiniferatoxin, NADA (N-arachidonyldopamine), OLDA (N-oleildopamine), olvanil, and PPAHV (holball 12). Causes of pain development to minimize the potential adverse consequences of activation and / or injury of C and / or Adelta fibers outside the pain site (-phenylacetate 13-acetate 20-homovanirate) Refers to any compound that results in the disruption or incapacity of selective and highly localized C and / or Adelta fibers in a separate localized region. Other capsaicinoids suitable for use described herein include N-vanillyl nonanamide, N-vanillyl sulfonamide, N-vanillyl urea, N-vanillyl carbamate, N-[(substituted phenyl) methyl] alkylamide. , N-[(substituted phenyl) methyl] alcanamide substituted with methylene, N-[(substituted phenyl) methyl] -cis-monosaturated alkenamide, N-[(substituted phenyl) methyl] di-unsaturated amide, 3 -Hydroxyacetanilide, hydroxyphenylacetamide, pseudocapsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin I, anandamide, piperin, zingeron, walburganar, polygodial, aframodial, sinnamodial (Cinnamosmolide), cinnamolide, civainde, nonivamide, N-oleyl-homovanillamidia, isovanillamidia, isovarianllamidia, isovellardia, scalad. , Β-Acaridial, merulidial, scutigeral, and any combination or mixture thereof, but is not limited to these.

The term "TRPV1 agonist" as used herein refers to a compound or composition that activates the transient receptor potential vanilloid 1 receptor (TRPV1). TRPV1 agonists include, but are not limited to, capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, dihydrocapsaicin, nonibamide, and resiniferratoxin.

The term "effective amount" or "therapeutically effective amount", as used herein, is sufficient to relieve one or more symptoms of the disease or disease being treated. Represents a quantity. As a result, signs, symptoms, or causes of the disease can be reduced and / or alleviated, or other desirable changes in the biological system can be brought about. For example, a therapeutic "effective amount" is the amount of a composition comprising a compound of formula (I) or (II) described herein. This compound is required to clinically significantly reduce the symptoms of the disease. Appropriate and "effective" amounts may be determined in any case using techniques such as dose-increasing studies.

The term "enhancement" or "enhancing" means, as used herein, an increase or extension of the desired effect in either efficacy or duration. Thus, with respect to enhancing the efficacy of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the effect of another therapeutic agent on the system, either in efficacy or duration. As used herein, "amount effective for enhancement" refers to an amount appropriate to enhance the effect of another therapeutic agent in the desired system.

As used herein, the term "co-administration" etc. means to include the administration of a selected therapeutic agent to a single patient, with the same or different routes of administration, or the same or different duration of administration. It is intended to include a treatment regimen to which the drug is administered by.

The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the incorporation of a compound into a cell or tissue.

The term "diluter" refers to a chemical compound used to dilute a compound of interest prior to delivery. Diluents can also be used to stabilize compounds as they can provide a more stable environment. Salts dissolved in a buffer (which can also regulate or maintain pH) are used as diluents in the art, including, but not limited to, phosphate buffered physiological saline.

A "metabolite" of a compound disclosed herein is a derivative of the compound formed during the metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound that is formed during the metabolism of the compound. The term "metabolized", as used herein, refers to the entire process by which an organism changes a particular substance, including but not limited to hydrolysis reactions and enzyme-catalyzed reactions. Point to. Therefore, the enzyme may bring about specific structural changes to the compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase activates to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Catalyzes the movement of glucuronic acid molecules. Detailed information on metabolism may be obtained from "The Pharmacological Basics of Therapeutics, 9th Edition, McGraw-Hill (1996)". The compound metabolites disclosed herein are either by administration of the compound to the host and analysis of tissue samples taken from the host, or by in vitro incubation of the compound by hepatocytes and analysis of the resulting compound. Can be identified by.

"Bioavailability" refers to the weight percent of a compound disclosed herein (eg, a compound of formula (I) or (II)), which is delivered to the animal or human being studied and circulated systemically. Total drug exposure (AUC (0-∞)) when administered intravenously is usually defined as 100% available to the organism (F%). "Oral bioavailability" refers to the extent to which the compounds disclosed herein are absorbed and circulated systemically when the pharmaceutical composition is taken, when compared to intravenous injection.

"Plasma concentration" refers to the concentration of a compound of formula (I) or (II) disclosed herein within the plasma component of a subject. It should be appreciated that plasma concentrations of the compounds described herein may vary significantly between subjects due to variability in metabolism and / or potential for interaction with other therapeutic agents. According to one embodiment disclosed herein, plasma concentrations of the compounds disclosed herein may vary from subject to subject. Similarly, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC (0-∞)) are per subject. It may fluctuate. Due to this variability, the amount required to construct a "therapeutically effective amount" of the compound may vary from subject to subject.

As used herein, "remission" refers to amelioration of a disease or disease, or at least partial relief of a disease or disease-related symptoms.

Pharmaceutical Compositions and Methods of Administration The pharmaceutical composition comprises one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the treatment of the active compound into a pharmaceutically usable preparation. It may be formulated in a conventional fashion using it. The appropriate formulation depends on the route of administration chosen. Further details regarding the excipients suitable for the pharmaceutical compositions described herein are described, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); John E. , Remington's Pharmaceutical Sciences, Mac Publishing Co., Ltd. , Easton, Pennsylvania 1975; Liberman, H. et al. A. and Lachman, L. et al. , Eds. , Pharmaceutical Dose Forms, Marcel Dekker, New York, N. et al. Y. , 1980; and Physical Dose Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), these documents are cited herein by reference for disclosure.

Pharmaceutical compositions, as used herein, are formulated with other chemical components such as carriers, stabilizers, diluents, dispersants, suspensions, thickeners, and / or excipients. Refers to a mixture with the compound of I) or (II). The pharmaceutical composition facilitates administration of the compound to an organism. In performing the procedures or methods of use provided herein, a therapeutically effective amount of a compound described herein is intended for the subject to be treated with the disease, disorder, or disease. It is administered as contained in the pharmaceutical composition. In some embodiments, the subject is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compounds used, and other factors. The compounds of formula (I) or (II) can be used alone or in combination with one or more therapeutic agents (such as in combination therapy) as a component of a mixture.

The pharmaceutical formulations described herein include oral, parenteral (eg, epidural, intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. It can be administered to a subject by a plurality of routes of administration not limited to these. Further, the pharmaceutical composition described herein contains a compound of formula (I) or (II) described herein and can be formulated into any suitable dosage form. This dosage form includes water-soluble oral dispersants, liquids, gels, syrups, elixirs, slurrys, suspensions, aerosols, release-controlled formulations, fast-dissolving formulations, foaming formulations, lyophilized formulations, tablets, powders, rounds, Examples thereof include, but are not limited to, sugar-coated tablets, capsules, delayed-release preparations, continuous-release preparations, pulse-release preparations, multifine particle preparations, and mixed immediate-release / controlled-release preparations.

One of ordinary skill in the art may administer the compound and / or the composition by a topical method rather than systemically, for example by direct injection of the compound into an organ or tissue, often in the form of a Devo formulation. Such formulations may be administered by implantation (eg, subcutaneous or intramuscular) or by intramuscular injection. In addition, the drug may be provided in the form of a rapid release formulation, a sustained release formulation, or an intermediate release formulation.

Pharmaceutical compositions containing the compounds described herein are, by way of example, produced in a conventional manner by conventional mixing, dissolving, granulating, sugar-coated tablet production, powdering, emulsifying, encapsulation, encapsulation, compression processes and the like. May be done.

The pharmaceutical composition comprises at least one of the compounds of formula (I) or (II) described herein as an active ingredient in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. include. In addition, the methods and pharmaceutical compositions described herein include the use of active metabolites and crystalline forms (also known as polymorphs) of these compounds with the same type of activity. Depending on the circumstances, the compound may exist as a tautomer. All tautomers are included within the scope of the compounds described herein. In addition, the compounds described herein can exist not only in non-solvate forms, but also in solvated forms containing pharmaceutically acceptable solvents such as water, ethanol and the like. Solvation forms of the compounds presented herein are also considered as disclosed herein.

In certain embodiments, the compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, cetylpyridinium chloride.

Pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more of the compounds described herein (eg, compounds of formula (I) or (II)). It can be obtained by optionally grinding the resulting mixture, treating the mixture of granules, adding the appropriate excipients if desired, and then producing tablets, pills, or capsules. Fillers such as sugars containing, for example, lactose, sucrose, mannitol, or sorbitol as suitable excipients; for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacant gum, methyl cellulose, microcrystalline cellulose, hydroxypropyl. Cellulose preparations such as methyl cellulose, sodium carboxymethyl cellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant such as crosslinked sodium croscarmellose, polyvinylpyrrolidone, agar, or a salt of alginic acid such as alginic acid or sodium alginate may be added.

The sugar-coated core is properly coated. Concentrated sugar solutions are used for this purpose. The concentrated sugar solution may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or dyes may be added to the tablet or dragee coating to identify or characterize various combinations of dosages of the active compound.

Orally usable pharmaceutical preparations include indentation capsules made of gelatin, as well as plasticizers such as glycerol or sorbitol and soft sealed capsules made of gelatin. Push-in capsules can contain active ingredients in admixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. .. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein are tablets (including suspension tablets, fast-dissolving tablets, bite-disintegrating tablets, rapidly disintegrating tablets, effervescent tablets, or caplets), rounds. , Powders (including sterile packaged powders, dispenseable powders, or foamed powders), capsules (including both soft and hard capsules: for example capsules made from animal-derived gelatin or plant-derived HPMC, or It may be in the form of "sprinkle capsule", solid dispersion, solid solution, biodegradable dosage form, controlled release formulation, pulse release dosage form, multiparticle dosage form, pellet preparation, granules, or aerosol. In embodiments, the pharmaceutical product is in the form of a powder, and in other embodiments, the pharmaceutical product is in the form of a tablet, including, but not limited to, a fast-dissolving tablet. Further, of the compounds described herein. The pharmaceutical product may be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical product is administered in 2, 3 or 4 capsules or tablets.

In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, mix particles of the compounds of formula (I) or (II) described herein with one or more pharmaceutical excipients. It is prepared by forming a bulk mixed composition. When these bulk mixed compositions are referred to as homogeneous, it is that the particles of the compound of formula (I) or (II) described herein are uniformly dispersed in the composition, resulting in the composition being tablets, pills. It means that it may be subdivided into unit dose forms with equal effect, such as capsules. Individual unit doses may further include a film coating that disintegrates after oral ingestion or contact with diluent. Such formulations can be produced by conventional pharmacological techniques.

The pharmaceutical solid dosage forms described herein are a combination of a compound of formula (I) or (II) described herein with one or more pharmaceutically acceptable additives such as a compatible carrier, binding. Agents, fillers, suspensions, flavors, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moisturizers, plasticizers, stabilizers, penetration enhancers , Wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. In yet another embodiment, a film coating is applied around the formulation of the compound described herein using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). .. In one embodiment, some or all of the particles of the compounds described herein are coated. In another embodiment, some or all of the particles of the compounds described herein are microencapsulated. In yet another embodiment, the particles of the compounds described herein are neither microencapsulated nor coated.

Suitable carriers for use in the solid dosage forms described herein include acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soybean lecithin, chloride. Sodium, tricalcium phosphate, dipotassium phosphate, stearoyl lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, etc. However, it is not limited to these.

Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium dibasic phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate. , Dextran, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMACAS), glucose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc. Be done.

Disintegrants are often used to release compounds of formula (I) or (II) from the solid dosage form matrix as efficiently as possible, especially when the dosage form is compressed by a binder. Disintegrants help rupture the dosage form matrix by swelling or capillarity as water is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage form described herein include natural starches such as corn starch and potato starch, pregelatinized starches such as National1551 and Amijel®, or Polymer®. Sodium starch glycolate such as Explotab®, cellulose such as wood products, methyl crystalline cellulose (eg, Avicel®, Avicel® PH101, Avicel® PH102, Avicel®. ) PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methyl cellulose, croscarmellose, or cross-linked cellulose, eg, cross-linked. Cross-linked polyvinylpyrrolidone, arginate, cross-linked polymer such as sodium carboxymethyl cellulose (Ac-Di-Sol®), cross-linked carboxymethyl cellulose, or cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, for example crospovidone. Clays, gums such as Veegum® HV (aluminum magnesium silicate), such as, for example, alginic acid or salts of sodium alginate, such as agar, guar, locust bean, karaya, pectin, or tragant, sodium starch glycolate, bentonite, Examples thereof include, but are not limited to, natural sponges, surfactants, resins such as cation exchange resins, citrus flesh, sodium lauryl sulfate, and sodium lauryl sulfate combined with starch.

The binder imparts stickiness to the solid oral dosage form. For powder-filled capsule formulations, this formulation aids in the formation of fillable stoppers in soft-shell or hard-shell capsules, while for tablet formulations, ensuring that the tablets remain intact after compression and compression. Alternatively, it helps to ensure uniform mixing before the filling process. Suitable materials for use as binders in the solid dosage forms described herein include carboxymethyl cellulose, methyl cellulose (eg, Methyl cellulose®), hydroxypropyl methyl cellulose (eg, Hypromellose USP Pharmacoat-603, hydroxypropylmethyl cellulose acetate). Stearate (Aquarate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (eg Klucel®), ethyl cellulose (eg Ethocel®), and microcrystalline cellulose (eg Avicel®). , Microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragant, dextrin, sugar, eg sucrose (eg Dipac) (Registered Trademarks)), glucose, dextrose, sugar honey, mannitol, sorbitol, xylitol (eg Xylitab®), lactose, natural or synthetic rubbers such as acacia, tragant, gatigam, isapol husks mucilage, starch. , Polyvinylpyrrolidone (eg, Povidone® CL, Kollidon® CL, Polyplasmdone® XL-10, and Povidone® K-12), Karamatsu alabocalactan, Veegum. (Registered Trademark), polyethylene glycol, wax, sodium alginate and the like can be mentioned, but the present invention is not limited thereto.

Generally, 20-70% binder level is used for the powder-filled gelatin capsule formulation. The level of use of the binder in the tablet formulation is either direct compression, wet granulation, roller compression, or other excipients such as fillers that can themselves act as moderate binders. It fluctuates. In some embodiments, the formulation determines the binder level of the formulation, and a binder usage level of up to 70% is common in tablet formulations.

Stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metals and alkaline earth metal salts as lubricants or flow promoters suitable for use in the solid dosage form described herein. , Aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, Alternatively, methoxypolyethylene glycol such as Carbowax®, PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostaterate, glyceryl benzoate, magnesium, or sodium lauryl sulfate, etc. However, it is not limited to these.

Suitable diluents for use in the solid dosage form described herein include sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrate and dextrin), polyols (mannitol, xylitol). , And sorbitol), cyclodextrin, and the like, but are not limited thereto.

Suitable wetting agents for use in the solid dosage form described herein include, for example, oleic acid, glycerin monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan mono. Oleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (eg Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium doxart, triacetin, vitamin E TPGS, etc. Be done.

Suitable surfactants for use in the solid dosage form described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, monostearic acid. Examples include glycerin, a copolymer of ethylene oxide and propylene oxide, such as Pluronic® (BASF).

Polyvinylpyrrolidone (eg, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30), polyethylene glycol (eg, polyethylene glycol is about. (With a molecular weight of 300 to about 6000, about 3350 to about 4000, or about 5400 to about 7000), vinylpyrrolidone / vinylacetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate 80, hydroxyethylcellulose, Sodium alginate, gum (eg, tragacant gum, acacia gum, guar gum, xanthan containing xanthan gum), saccharides, cellulose-based ones (eg, sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, etc.), polysorbate 80 , Polyethoxylate sorbitan monolauric acid, polyethoxylate sorbitan monolauric acid, povidone and the like, but are not limited thereto.

Suitable antioxidants for use in the solid dosage form described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

There is considerable overlap between the additives used in the solid dosage forms described herein. Therefore, the additives listed above are merely illustrations of the types of additives that can be included in the solid dosage forms of the pharmaceutical compositions described herein and should not be construed as limiting.

In other embodiments, one or more layers of the pharmaceutical product are plasticized. Illustratively, the plasticizer is usually a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% by weight to about 50% by weight (w / w) of the coating composition. Plasticizers include diethyl phthalate, citrate ester, polyethylene glycol, glycerol, acetylated glyceride, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil. However, it is not limited to these.

Compressed tablets are solid dosage forms prepared by compression of large mixtures of the above-mentioned formulations. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavorings. In another embodiment, the compressed tablet comprises a film that surrounds the compressed tablet finished product. In some embodiments, film coating can delay the release of the compound of formula (I) or (II) described herein from the pharmaceutical product. In other embodiments, the film coating aids patient compliance (eg, Opadry® coating or sugar coating). Film coatings containing Opadry® typically range from about 1% to about 3% by weight of tablets. In other embodiments, the compressed tablet comprises one or more excipients.

Capsules may be prepared, for example, by placing a large mixture of the above-mentioned compound formulations inside the capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the pharmaceutical product is placed in standard gelatin capsules or non-gelatin capsules, such as capsules containing HPMC. In another embodiment, the formulation is placed in a sprinkle capsule, where the capsule may be swallowed in its entirety, or the capsule may be opened and its contents sprinkled on food prior to meals. In some embodiments, the therapeutic dose is divided into multiple (eg, 2, 3, or 4) capsules. In some embodiments, the entire dose of the pharmaceutical product is delivered in capsule form.

In various embodiments, the particles of the compound of formula (I) or (II) described herein and one or more excipients are dried and mixed and compressed into lumps such as tablets. This mass is almost decomposed within about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration. Has sufficient hardness to provide a pharmaceutical composition that releases the formulation into gastrointestinal fluid.

In another aspect, the dosage form may comprise a microencapsulated formulation. In some embodiments, one or more compatible materials are present in the microencapsulated material. Typical materials include pH regulators, erosion promoters, defoamers, antioxidants, flavors, as well as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers. , But not limited to, carrier materials such as lubricants, wetting agents, and diluents.

Materials useful for microencapsulation described herein include materials compatible with the compounds described herein that adequately separate the compound from other incompatible excipients. Materials compatible with the compounds described herein are materials that delay the release of the compound of formula (I) or (II) in vivo.

Hydroxypropyl cellulose ethers (HPCs) such as Klucel® and Nisso HPC, low-substituted hydroxypropyl cellulose ethers, as typical microencapsulating materials that help delay the release of formulations containing the compounds described herein. (L-HPC), Seppifilm-LC, Polymercoat®, Polymerose SR, Polymer®-E, Opadry YS, PrimaFlo, Benecel MP824, Benecel MP843, etc. Hydroxypropyl Methyl Cellulose Ether (HPC) Methyl Cellulose Polymers such as-A, Hydroxypropyl Methyl Cellulose Acetate Steerate Aquot (HF-LS, HF-LG, HF-MS), Methylrose®, Ethyl Cellulose (EC) and Mixtures thereof, such as E461, Ethocel (Registered). Salts of hydroxyethyl cellulose, carboxymethyl cellulose and carboxymethyl cellulose (CMC) such as Polymer), Aqualon®-EC, Surerease®, Polyvinyl alcohol (PVA) such as Polymer AMB, Natrosol®, eg, Aqualon. (Registered Trademarks)-Polyvinyl alcohol and polyethylene glycol copolymers such as CMC, such as Kollicaat IR®, Myverol, Triglyceride (KLX), Polyethylene Glycol, Modified Food Steel, Acrylic Polymers, and Acrylic Polymers and Eudragit (Registered Trademarks). Registered Trademarks) EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100 , Polymer® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D mixtures with cellulose ethers, acetic acid. Sepifilms such as cellulose phthalate, a mixture of HPMC and stearic acid. , Cyclodextrin, and mixtures of these materials, but are not limited thereto.

In yet another embodiment, a plasticizer such as polyethylene glycol, such as PEG300, PEG400, PEG600, PEG1450, PEG3350, PEG800, stearic acid, propylene glycol, oleic acid, triacetin, is incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical composition is from the USP or National Pharmaceuticals Collection (NF). In yet another embodiment, the microencapsulating material is Klucel. In yet another embodiment, the microencapsulating material is methyl.

The microencapsulated compounds described herein are, for example, spray drying process, rotary disk solvent process, thermal melting process, spray lowering method, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, etc. It may be formulated by a method comprising polymerization at a liquid-gas or solid-gas interface, pressure extrusion, or a spray solvent extraction bath. In addition to these, various chemical techniques such as composite core selvation, dissolution evaporation, incompatibility between polymers, interfacial polymerization in liquid media, insights polymerization, in-liquid drying methods, and desolvation in liquid media are also used. be able to. In addition, other methods such as roller compression, ejection / spheroidization, core selvation, or nanoparticle coating may also be used.

In other embodiments, foamed powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse the drug in water for oral administration. The effervescent salt is a granule or coarse powder containing a drug in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When these salts are added to water, the acid and base react to liberate carbon dioxide, thereby causing "foaming". Examples of effervescent salts include, for example, the following components: sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartrate acid. Any acid-base combination that results in the release of carbon dioxide is a combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher. Can be used instead of.

In another embodiment, the pharmaceutical product described herein comprises a compound described herein and is a solid dispersant. As a method for producing such a solid dispersant, for example, US Pat. Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723 , 269, and US Patent Publication No. 2004/0013734, but is not limited thereto. In still other embodiments, the formulations described herein are solid solutions. The solid solution incorporates a substance that integrally contains the active agent and other excipients, thereby heating the mixture, resulting in dissolution of the drug and later cooling of the resulting composition. , Further formulated, added directly to the capsule, or resulting in a compressible solid mixture into tablets. Examples of methods for producing such a solid solution include, but are not limited to, US Pat. Nos. 4,151,273, 5,281,420, and 6,083,518.

Solid pharmaceutical oral dosage forms containing the formulations described herein contain the compounds described herein and are further formulated to provide a controlled release of the compound of formula (I) or (II). be able to. Controlled release refers to the release of said compound from a dosage form in which the compounds described herein are incorporated according to the desired properties over a long period of time. Controlled emission characteristics include, for example, sustained emission, long-term emission, pulse emission, and delayed emission characteristics. In contrast to the immediate release composition, the controlled release composition allows long-term delivery of the drug to the subject according to predetermined properties. Such release rates can provide therapeutically effective levels of the drug over a long period of time, thus resulting in a longer term pharmacological response with minimal side effects compared to traditional rapid release dosage forms. It is suppressed to. These long-term reactions provide many inherent benefits not achieved with the corresponding short-acting immediate release preparations.

In some embodiments, the solid dosage form described herein is an enteric coated delayed release oral dosage form, i.e., enteric to affect the release of the gastrointestinal tract into the small intestine. It can be formulated as an oral dosage form of a pharmaceutical composition as described herein utilizing a coating. The enteric coated dosage form is compressed, containing berries, powders, pellets, beads, or microparticles of active and / or other compositional ingredients that are or are not coated by themselves. , Molded or extruded tablets / molds (coated or uncoated). Oral dosage forms with an enteric coating are also capsules (coated or uncoated) containing pellets, beads, or granules of solid carriers or compositions that are themselves coated or uncoated. May be.

As used herein, the term "rapid release" or "delayed release" refers to delivery such that release can be achieved at some normally predictable rates. In some embodiments, the method of delaying release is by regulating the intramolecular cyclized release reaction or by adding a buffer to modify the initiation of the intramolecular cyclized release reaction.

Colorants, detachfires, surfactants, defoamers, lubricants (eg carnauba wax or PEG) are produced to solubilize or disperse the coating material and with coating performance and coating. In addition to the plasticizer, it may be added to the coating to improve the product.

In other embodiments, the formulations described herein comprise a compound of formula (I) or (II) described herein and is delivered using a pulsed dosage form. The pulse dosage form can provide one or more immediate emission pulses at a given time point after preparation of the delay time or at a particular site. The pulsed dosage form is not limited to the following US patents: US Pat. Nos. 5,011,692, 5,017,381, 5,229,135, 5,840,329, 4,871, Various pulse formulations including those described in 549, 5,260,068, 5,260,069, 5,508,040, 5,567,441, and 5,837,284. May be administered using.

Many other types of controlled release systems are suitable for use with the formulations described herein. Examples of such delivery systems are polylactic acid and polymers derived from polymers such as polyglycolic acid, polyacid anhydrides, polycaprolactone; sterols such as cholesterol, cholesterol esters and fatty acids, or triglycerides such as monoglycerides and diglycerides. , And triglycerides, lipid porous matrices, non-polymer derived systems; hydrogel-releasing systems; silastic systems; peptide-derived systems; wax coatings, biodegradable dosage forms, compression using conventional binders. Examples include tablets. For example, Liberman et al. , Pharmaceutical Dosage Forms, 2 Ed. , Vol. 1, pp. 209-214 (1990); Singh et al. , Encyclopedia of Physical Technology, 2nd Ed. , Pp. 751-753 (2002); US Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140; 5,456,923; No. 5,516,527; No. 5,622,721; No. 5,686,105; No. 5,700,410; No. 5,977,175; No. 6,465,014; See 6,932,983.

In some embodiments, it comprises particles of a compound described herein, eg, a compound of formula (I) or (II), and at least one dispersant or suspension for oral administration to a subject. Pharmaceutical formulations are provided. This formulation may be powder and / or granules for suspension, resulting in a substantially uniform suspension after mixing with water.

Dosage forms of liquid formulations for oral administration are selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. It may be a turbid liquid. For example, Singh et al. , Encyclopedia of Physical Technology, 2nd Ed. , Pp. See 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain homogeneous as defined in the USP Pharmacopoeia (2005 edition, Chapter 905) for at least 4 hours. This homogeneity needs to be determined by a consistent sampling method for determining the homogeneity of the entire composition. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, no agitation is required to maintain a homogeneous dispersed aqueous solution.

The pharmaceutical compositions described herein are, but are not limited to, acacia syrup, acesulfame K, ariterm, anis, apple, aspartame, banana, bavaroa, berry, cassis, butterscotch, calcium citrate, camphor, caramel, cherry, cherry. Cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton confectionery, cocoa, cola tree, cool cherry, cool citrus, cyclamate, silamate, sucralose, eucalyptus, eugenol, fructose, fruit punch, ginger, green Glycyrrhetinate, saccharin syrup, grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltall, mannitol, maple, marshmallow. , Mentor, Mint Cream, Mixed Berry, Neo Hesperidin DC, Neo Tame, Orange, Western Pear, Peach, Peppermint, Peppermint Cream, Prosweet® Powder, Raspberry, Rootvia, Lamb, Saccharin, Saffralose, Solbitol, Sparemint, Sparemint Cream , Strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatos, tangerine, taumatin, tuttifrutti, vanilla, walnuts, watermelon, American cherry , Winter green, xylitol, or any combination of these flavoring ingredients, such as acesulfame, cherry-anis, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint. , Mentor-eucalyptus, orange-cream, vanilla-mint, and sweeteners such as mixtures thereof may be included.

In some embodiments, the pharmaceutical formulation described herein may be a self-emulsifying drug delivery system (SEDDS). An emulsion is a dispersion of one immiscible phase in another form, usually in the form of droplets. Emulsions are usually made by vigorous mechanical dispersion. SEDDS, in contrast to emulsions or microemulsions, spontaneously form emulsions when added to excess water without the need for any external mechanical dispersion or agitation. The advantage of SEDDS is that only a light mix is required to distribute the droplets throughout the solution. In addition, water or aqueous phase can be added immediately prior to administration, which ensures the stability of the unstable or hydrophobic active ingredient. Therefore, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can bring about an improvement in the bioavailability of the hydrophobic active ingredient. Methods of producing the self-emulsifying form include, but are not limited to, US Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

There is overlap between the additives listed above used in the aqueous dispersions or suspensions described herein. The reason is that a given additive is often classified differently by different skill in the art or commonly used for any of different functions. Therefore, it should be construed that the additives listed above are merely exemplary and not limited to the types of additives that may be included in the formulations described herein.

Excipients that can be used for intranasal formulations include, for example, US Pat. Nos. 4,476,116, 5,116,817, and 6,391,452. A solution of the formulation in saline using a suitable preservative such as benzyl alcohol, fluorocarbons, and / or other solubilizers or dispersants. For example, Ansel, H. et al. C. et al. , Pharmaceutical Dose Forms and Drug Delivery Systems, Sixth Ed. See (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic, pharmaceutically acceptable ingredients. The choice of suitable carrier depends largely on the exact properties of the desired nasal dosage form, eg solutions, suspensions, ointments, gels. The nasal dosage form as a whole contains a large amount of water in addition to the active ingredient. Small amounts of other ingredients such as pH regulators, emulsifiers or dispersants, preservatives, surfactants, gelling agents, or buffers, and other stabilizers and solubilizers may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

For administration by inhalation, the compounds described herein may be in the form of aerosols, mists, or powders. The pharmaceutical compositions described herein are aerosols from a pressure pack or atomizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Conveniently delivered in the form of a spray delivery. For pressurized aerosols, the dosing unit may be determined by providing a valve to deliver the measured amount. Gelatin capsules and cartridges, as just one example, used in inhalers or inhalers are formulated containing a powder mixture of the compounds described herein with a suitable powder substrate such as lactose or starch. May be.

Buccal formulations containing the compounds described herein include, but include, US Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. It may be administered using various formulations without limitation. In addition, the buccal dosage forms described herein can further comprise a biodegradable (hydrolyzable) polymer carrier that also serves to attach the dosage form to the buccal mucosa. The buccal dosage form is designed to gradually corrode over a given period of time, where delivery of the compound is provided almost entirely. Buccal drug delivery avoids the disadvantages faced by oral drug administration, such as slow absorption, degradation of the active drug by fluids in the gastrointestinal tract, and / or inactivation of first pass in the liver. For biodegradable (hydrolyzable) polymer carriers, the carrier is compatible with the compounds described herein and other components present in buccal dose units, as long as the desired drug release properties are not compromised. In effect, such carriers can be used as long as they have sex. Usually, the polymer carrier is a hydrophilic (water-soluble and water-swellable) polymer that adheres to the moist surface of the buccal mucosa. Examples of useful polymer carriers herein include acrylic acid polymers and copolymers (co), such as those known as "carbomer" (Carbopol® available from BF Goodrich). Is a type of such polymer). Other ingredients may be incorporated into the buccal dosage forms described herein, including but not limited to disintegrants, diluents, binders, lubricants, flavors, colorants, preservatives and the like. For buccal or sublingual administration, the composition may be in the form of tablets, lozenges, or gels formulated by conventional methods.

The transdermal formulations described herein are U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951 and 3, , 814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4, 060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336 , 168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801, and 6,946,144. It may be administered using various devices including, but not limited to.

The transdermal dosage forms described herein may incorporate pharmaceutically acceptable excipients that are prior art in the art. In one embodiment, the transdermal formulation described herein comprises at least three components: (1) a formulation of a compound of formula (I) or (II), (2) a penetration promoter, and (3) an aqueous adjuvant. And include. In addition, the transdermal formulation can include additional ingredients including, but not limited to, gelling agents, creams, ointment bases and the like. In some embodiments, the transdermal formulation may further comprise a woven or non-woven lining material to enhance absorption and prevent removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can remain saturated or supersaturated to facilitate dispersion over the skin.

Suitable formulations for transdermal administration of the compounds described herein may use transdermal delivery devices and transdermal delivery patches, and are soluble and / or dispersed in polymers or adhesives, lipophilic. It may be a strong emulsion or a buffered aqueous solution. Such patches may be constructed for continuous delivery, pulse delivery, or on-demand delivery of medicinal products. Furthermore, transdermal delivery of the compounds described herein is feasible, such as by iontophoresis patches. In addition, transdermal patches can provide controlled delivery of the compounds described herein. The rate of absorption can be slowed by using a rate-determining membrane or by trapping the compound in a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. The absorption enhancer or carrier can include a pharmaceutically acceptable absorbent solvent to assist in passage through the skin. For example, a transdermal device may include a lining member, a reservoir containing a compound optionally including a carrier, and a speed control barrier for delivering the compound to the skin of the host at a controlled rate and a predetermined rate for an optional long period of time. It is in the form of a bandage that includes a means of fixing the device to the skin.

Suitable formulations for intramuscular, subcutaneous, or intravenous injection are into physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile injection solutions or dispersions. May contain sterile powders that are reconstituted with. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles are water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremofol, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.). ), As well as injectable organic acid esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the desired particle size in the case of dispersions, and the use of surfactants. Suitable formulations for subcutaneous injection may include additives such as preservatives, wetting agents, emulsifying agents, and distributors. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanols, phenols, sorbic acids. It may be desirable to include isotonic agents such as sugar and sodium chloride. Long-term absorption of injectable dosage forms can be triggered by the use of drugs that delay absorption, such as aluminum monostearate and gelatin.

For intravenous injection, the compounds described herein are formulated in aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or buffered saline. May be good. For oral mucosal administration, a penetrant suitable for the penetrating barrier is used in the formulation. Such penetrants are generally recognized in the art. For other parenteral infusions, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the art.

Parenteral injections may require bolus or continuous injections. The pharmaceutical product for injection may be provided in a unit dosage form with an additional preservative, for example in an ampoule or a multi-dose container. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and are suspending agents, stabilizers, and the like. And / or a formulation such as a dispersant may be included. Pharmaceutical formulations for parenteral administration include an aqueous solution of the active compound in water-soluble form. In addition, suspensions of active compounds may be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxylmethylcellulose, sorbitol, or dextran. In some cases, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of high concentration solutions. Alternatively, the active ingredient may be in powder form to construct a suitable vehicle prior to use, eg, sterile distilled water free of pyrogens.

In certain embodiments, delivery systems for pharmaceutical compounds such as liposomes and emulsions may be used. In certain embodiments, the compositions described herein are, for example, carboxymethyl cellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbofyl, acrylic acid / butyl acrylate copolymer, arginic acid. It further comprises a mucoadhesive polymer selected from among sodium and dextran.

In some embodiments, the compounds described herein may be administered topically, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, sedatives, creams, or ointments. It is formulated into a variety of topically administrable compositions. Such pharmaceutical compounds can include solubilizers, stabilizers, tonicity promoters, buffers, and preservatives.

The compounds described herein are enema agents, rectal gel agents, rectal foams, rectal aerosols, suppositories, including conventional suppository bases such as glycerides such as cocoa butter and synthetic polymers such as polyvinylpyrrolidone (PEG). , Jelly suppository, or a rectal composition such as a retention enema may be incorporated and formulated. In the suppository form of the composition, the low melting point wax is, but is not limited to, a mixture of fatty acid glycerides, and in some cases, melts first in combination with cocoa butter.

Drugs, such as compounds of formula (I) or (II), are usually administered in effective amounts (ie, therapeutically effective amounts) to ameliorate the disease or disorder or to prevent the progression of symptoms of the disease or disorder. NS. Therefore, a therapeutically effective amount may be an amount capable of at least partially preventing or reversing the disease or disorder. The dose required to obtain an effective amount may vary depending on the drug, formulation, disease or disorder, and the individual to whom the drug is administered.

Determining the effective amount may require in vitro analysis, in which various doses of the drug are administered to cells in culture and partly to calculate the concentration required in vivo. Or the concentration of a drug that is effective in relieving all symptoms is sought. Effective amounts may be based on in vivo animal studies.

The drug can be administered before, at the same time as, and after the onset of symptoms of the disease or disorder. In some embodiments, the agent is given to a subject with a family history of the disease or disorder, a subject with a phenotype capable of predisposing to the disease or disorder, or a subject with a genotype susceptible to the disease or disorder. Be administered.

The particular delivery system used may depend on many factors, including, for example, the intended target and route of administration (eg, local or systemic). The target of delivery may be the specific cell causing or causing the disease or disorder. For example, the target cell may be a resident or infiltrating cell in the nervous system that is responsible for the neurological, neurodegenerative, or demyelinating disease or disorder. Administration of the agent may be targeted at one or more types or subgroups of cell types by methods recognized in the art. For example, the drug is selected for a virus that binds to a ligand for an antibody, cell surface receptor or toxin, or for a cell, such as a liposome, or a virus to which a viral receptor specifically binds to a particular cell type, or a viral particle lacking a viral nucleic acid. It can be contained in particles that are internally internalized or administered topically.

Dosing Methods and Treatment Regimen The compounds described herein can be used for the preparation of drugs for TRPV1 regulation or for the treatment of diseases or disorders that at least partially benefit from TRPV1 regulation. In addition, methods of treating any of the diseases or illnesses described herein are in at least one compound described herein, or pharmaceutically acceptable thereof, in a subject in need of such treatment. It comprises administering to a subject a pharmaceutical composition comprising a possible salt, a pharmaceutically acceptable solvate, or a hydrate in a therapeutically effective amount.

Compositions comprising the compounds described herein can be administered for prophylactic and / or therapeutic treatment. For therapeutic use, the composition is administered to a patient already suffering from a disease or disease in an amount sufficient to cure or at least partially prevent the disease or symptoms of the disease. The effective amount for this use will depend on the severity and course of the disease or illness, previous treatment, patient health, weight, and response to the drug, as well as the judgment of the attending physician.

For prophylactic applications, compositions containing the compounds described herein are administered to patients who are susceptible to or at risk of a particular disease, disorder, or disease. Such an amount is defined as a "preventive effective amount or dose". In this application, the exact amount also depends on the patient's health and weight. When used in a patient, an effective amount for this application is at the discretion of the disease, disorder, or severity and course of the disease, previous treatment, patient health, and response to the drug, as well as the treating physician. It will be affected.

At the discretion of the physician, administration of the compound is administered chronically, i.e. over a long period of time, including the entire life of the patient, to ameliorate the patient's disease or symptoms, or to control or limit.

At the discretion of the physician, the compound may be administered continuously. Alternatively, the dose of the drug administered is either temporarily reduced or temporarily stopped for a period of time (ie, a "drug holiday"). The period of drug holidays is just one example: 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days. Even if it fluctuates between 2 days and 1 year, including 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. good. Dose reductions during drug holidays are, as just one example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, Approximately 10% to approximately 100%, including approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, or approximately 100%. It may be done at.

Once improvement of the patient's illness occurs, maintenance doses are administered if necessary. The dose, frequency of administration, or both can then be reduced to a level at which the disease, disorder, or improvement of the disease is retained, depending on the symptoms. However, patients may require long-term, intermittent treatment when symptoms recur.

The amount of a given drug corresponding to such amount will vary depending on factors such as the particular compound, disease or disease and its severity, subject or host identity in need of treatment (eg, body weight). However, nevertheless, the art is in accordance with the particular environment surrounding the situation, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated. It can be determined by the method recognized by. However, in general, the doses used for the treatment of human adults typically range from about 0.001 mg to about 5000 mg per day, and in some embodiments from about 1 mg to about 1500 mg per day. The desired dose is conveniently provided as a single dose, or as a divided dose, simultaneously (or in a short period of time), or at appropriate intervals, eg, two, three, or four or more sub-administrations per day. It may be administered as an amount.

The pharmaceutical compositions described herein may be in unit dosage forms suitable for a single dose of the correct dose. In the unit dosage form, the pharmaceutical product is divided into unit doses containing an appropriate amount of one or more compounds. The unit dose may be in the form of a package containing a discrete dose of the pharmaceutical product. Non-limiting examples are powders in packaged tablets or capsules, vials or ampoules. The aqueous suspension composition can be packaged in a single volume container that cannot be resealed. Alternatively, a resealable container for multiple doses can be used, in which case it is common to include preservatives in the composition. As just one example, a formulation for parenteral injection may be provided in unit dosage form, including, but not limited to, ampoules, or multi-dose containers, along with additional preservatives.

Suitable daily doses for the compounds described herein are from about 0.001 mg / kg to about 30 mg / kg. In one embodiment, the daily dose is from about 0.01 mg / kg to about 10 mg / kg. The daily designated dose for large mammals, including but not limited to humans, ranges from about 0.1 mg to about 1000 mg, and is a single dose, but not limited to, divided doses including up to 4 times daily. Conveniently administered by volume or in sustained release form. Suitable unit dosage forms for oral administration contain about 1 to about 500 mg of active ingredient. In one embodiment, the unit dose is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. Due to the large number of variables for individual treatment regimens, the above range is merely suggestive and it is not uncommon to deviate significantly from these recommendations. These doses are many variables, but not limited to the activity of the compound used, the disease or disease being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disease being treated, and the physician. It may be changed depending on the judgment of.

The toxicity and therapeutic efficacy of these treatment regimens _{includes, but is limited to, measurements of LD 50} (lethal dose _{to 50% of the population) and ED 50} (therapeutically effective dose to 50% of the population). It can be determined by standard pharmaceutical procedures for cell culture or laboratory animals that are not. The dose ratio of toxic effect to therapeutic effect is the therapeutic index and can be expressed as the ratio of _{LD 50} to ED _50. Compounds with a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a series of doses used in humans. The dose of such compound is preferably within the range of blood concentrations including _{ED 50, which is minimally toxic.} This dose may vary within this range, depending on the dosage form utilized and the route of administration utilized.

Combination Treatment The compounds of formula (I) or (V), and compositions thereof, may also be used in combination with other therapeutic agents selected for the therapeutic value of the disease to be treated. In general, the compositions described herein, and in embodiments where combination therapy is used, other agents do not need to be administered in the same pharmaceutical composition and are various physical and chemical. Due to its characteristics, it needs to be administered by various routes. Determining the form of administration and the adequacy of administration is adequately made to the extent possible by the clinician in the same pharmaceutical composition, if possible. Initial administration can be performed according to established protocols recognized in the art and then modified by the clinician based on the observed effect, dose, dosage form, and frequency of administration.

In some cases, it may be appropriate to administer at least one of the compounds described herein in combination with another therapeutic agent. As just one example, if one of the side effects that occurs in a patient when administered one of the compounds described herein, such as formula (I) or (II), is vomiting, vomiting in combination with the first therapeutic agent. It may be preferable to administer an inhibitor. Or, as just one example, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (ie, the therapeutic benefit of the adjuvant alone is minimal, but with another therapeutic agent. The combination enhances the overall therapeutic benefit to the patient). Or, as just one example, the benefits a patient receives may be increased by administering one of the compounds described herein with another therapeutic agent (including a therapeutic regimen) that has therapeutic benefits. In all cases, regardless of the disease, disorder, or illness being treated, the overall benefit the patient receives is simply the additive effect of the two therapeutic agents, or the patient may have a synergistic effect. ..

In one example, a local anesthetic is used in combination with another therapeutic agent. As used herein, the term "local anesthetic" means a drug that relieves local numbness or pain. Typical examples of local anesthetics that can be used in combination with the present invention include bupivacaine, levobupivaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine.

In one example, a vasoconstrictor is used in combination with another therapeutic agent. Vasoconstrictors are useful and act locally to limit blood flow and thereby retain the infused drug in the area to which it is administered. This has the effect of substantially reducing systemic toxicity. Preferred vasoconstrictors are those that act on alpha adrenergic receptors such as epinephrine and phenylepinephrine.

In one example, the combination with another therapeutic agent uses glucocorticoids. Glucocorticoids include dexamethasone, cortisone, hydrocortisone, prednisolone, bechrometasone, betamethasone, flunisolide, methylprednisolone, parameterzone, prednisolone, triamcinolone, alchrometazone, amcinonide, clobetasol, fluocinolone, fluocinolone, fluocinolone, fluocinolone. It is selected from the group consisting of metholones, fluocorticoids, halcinonides, prednisolone, mommethasone, and pharmaceutically acceptable salts thereof, as well as mixtures.

In some embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or hydrate, is combined with a local anesthetic. Used.

In some embodiments, the compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, or hydrates, are with non-opioid analgesics. Used in combination.

The specific choice of compound used depends on the diagnosis of the attending physician and the judgment of the patient's condition and appropriate treatment protocol. The compounds may be simultaneous (eg, simultaneously, nearly simultaneously, or within the same treatment protocol) or consecutively, depending on the disease, disorder, or nature of the disease, the condition of the patient, and the actual choice of compound used. May be administered. The order of administration in the treatment protocol and the number of repeated doses of each therapeutic agent are within the range fully conceivable by the physician after assessing the disease being treated and the patient's condition.

When the drug is used for concomitant treatment, the therapeutically effective amount may vary. Methods for experimentally determining therapeutically effective doses of drugs and other agents for use in concomitant treatment regimens are described in the prior art literature. For example, the use of metronomic administration, ie providing high frequency and low doses to minimize toxic side effects, is widely described in the prior art literature. Combination treatments further include periodic treatments that are started and stopped at various time points to aid in the clinical management of the patient.

For the combination therapies described herein, the doses of co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or disease being treated, and the like. Become. In addition, when administered with one or more physiologically active materials, the compounds provided herein may be administered simultaneously or sequentially with the physiologically active agent. When administered serially, the attending physician will determine the appropriate order of administration of the protein in combination with a biologically active agent.

In any case, the plurality of therapeutic agents, one of which is a compound of formula (I) or (II) described herein, may be administered in any order or simultaneously. At the same time, the plurality of therapeutic agents may be provided in a single-use unified form or in multiple-time forms (as an example, as a single injection or two separate injections). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. If not simultaneous, the timing between multiple doses may vary from more than 0 weeks to less than 4 weeks. Moreover, the method, composition, and formulation of the combination is not limited to the use of only two agents. It is also envisioned to use multiple therapeutic combinations.

It should be understood that dosing regimens for treating, preventing, or ameliorating diseases that require palliative can be modified according to a variety of factors. These factors include the subject's age, weight, gender, diet, and medical condition, as well as the subject's disability. Therefore, the dosing regimen actually utilized may vary widely and may therefore deviate from the dosing regimen described herein.

The pharmaceuticals that construct the combination therapies disclosed herein may be a combination of dosage forms or individual dosage forms intended for near-simultaneous administration. The medications that construct the combination therapy may also be administered continuously, with either therapeutic agent being administered by a regimen that requires two-step administration. The two-step regimen may require continuous administration of the active agent or staggered administration of separate active agents. The period between multiple dosing steps may be minutes to hours, depending on the properties of each drug, such as efficacy, solubility, bioavailability, plasma half-life, dynamic properties, etc. of the drug. Changes in the daily cycle of target molecule concentration may also determine the optimal dosing interval.

In addition, the compounds described herein may be used in combination with treatments that have an additive or synergistic effect on the patient. As just one example, patients are expected to obtain therapeutic and / or prophylactic benefits in the methods described herein. In this case, the pharmaceutical composition of the compounds disclosed herein, and / or concomitant use with other therapeutic agents, is a carrier of the mutant gene in which the individual is known to correlate with a particular disease or disease. Combined with a genetic test to determine if.

The combination therapy with the compounds described herein can be administered before, during, or after the onset of the disease or disease, and the timing of administration of the composition containing the compound may vary. Thus, for example, a compound can be used as a prophylactic agent and can be continuously administered to a disease or subject who tends to progress the disease in order to prevent the onset of the disease or disease. The compounds and compositions can be administered to the subject during or as soon as possible after the onset of symptoms. Administration of the compound is within the first 48 hours of onset of symptoms, preferably within the first 48 hours of onset of symptoms, more preferably within the first 6 hours of onset of symptoms, most preferably within 3 hours of onset of symptoms. Can start at. Initial administration may be via any route, such as intravenous injection, bolus injection, injection over about 5 minutes to about 5 hours, pills, capsules, transdermal patches, buccal delivery, or a combination thereof. Can be done. The compound is preferably administered as soon as possible after the onset of the disease or illness is detected or suspected, and over the period requiring disease treatment, eg, about 1 day to about 3 months. The duration of treatment can be varied for each subject and this duration can be determined using known classification criteria. For example, the compound or the preparation containing the compound can be administered for at least 2 weeks, preferably about 1 month to about 5 years.

Kits / Products Kits and products are also described herein for use in the therapeutic applications described herein. Such kits may include carriers, packages, or containers with compartments for receiving one or more containers such as vials and tubes, each of which is described herein. Contains one of the separate elements used. Suitable containers include, for example, bottles, vials, syringes, test tubes. The container can be made of various materials such as glass and plastic.

For example, the container may contain one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container may optionally have a sterile access port (eg, the container may be a solution bag or vial for intravenous injection with a stopper through which a hypodermic needle can penetrate). Such kits, optionally with compounds, include identification instructions, labels, or instructions for use in the methods described herein.

Kits usually include one or more additional containers. Each includes one or more different materials (eg, optionally enriched forms of reagents and / or devices) that are desirable from a commercial and user point of view with respect to the use of the compounds described herein. Non-limiting examples of such materials include buffers, excipients, filters, needles, syringes; carriers, packages, containers, vials, and / or tube labels listing the contents and / or instructions for use, and Examples include, but are not limited to, package inserts that include instructions for use. A set of instructions is also usually included.

The label may be on top of the container or attached to the container. The label may be on top of the container if the letters, numbers, or other letters that form the label are bonded, molded, or engraved on the container itself. If present in a container or carrier holding the container, the label is attached to the container, for example as a package insert. Labels can be used to indicate that the content should be used for a particular therapeutic application. The label may further indicate instructions for use of the contents, such as by the methods described herein.

These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. The starting materials and reagents used in the synthesis of the compounds described herein may be synthesized, or Sigma-Aldrich Corp. , Across Organics, Fluka, Fisher Scientific, Arcpharm, Enamine Store, and Oakwood Chemicals, but are available from private sources.

Examples of Synthesis Example 1: (E) -2-methoxy-4-((8-methylnon-6-enamide) methyl) phenyl) 2-((methylamino) methyl) -4- (2,5,8) , 11-Tetraoxatetradecane-14-oil) Synthesis of piperazine-1-carboxylate (Compound 1)

Basic procedure 1 (Boc protection)
An Ar-purged 500 mL triple-necked RBF equipped with a stir bar, condenser, and Ar inlet was filled with an amine containing the starting material and iPrOH. After cooling to 0 ° C., _{a solution of Boc 2} O in iPrOH was added over 1 hour. The reaction was warmed to room temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (250 mL), organic phase was washed with a saturated solution of _{Na 2 CO 3 (3 × 250mL} ), dried over MgSO 4 (10 g), filtered through a Whatman # 4 filter paper in a vacuum The desired product was obtained by concentration.

Preparation of compound A:
Following the basic procedure 1, methyl (pyrazine-2-ylmethyl) amine (15.0 g, 121.8 mmol) was dissolved in iPrOH (125 mL), and Boc ₂ O (31.9 g, 146.2 mmol) was added to iPrOH. By reacting with a solution dissolved in (25 mL), compound A (29.2 g) was obtained as a brown oil. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ8.69-8.35 (m, 3H), 4.56 (apprentice d, J = 29.3Hz, 2H), 2.96 (apprentice d, J = 31.3Hz) , 3H), 1.45 (apprent d, J = 35.9Hz, 9H). LC-MS: m / z calcd for C ₁₁ H ₁₈ N ₃ O ₂ [M + H] ⁺ 224.1, observed 224.1.

Basic procedure 2 (hydrogenation):
A 2 L hydrogenated flask was filled with the starting material, 1,1,2-trichloroethane and methanol and sprayed with Ar for 1 hour. Pd / C a (10 wt%) and Pt / C (10wt%) was suspended in _{H 2} O, under Ar stream was carefully added to a hydrogenation flask. The reaction flask was shaken at _{70 psi H 2} for 72 hours on a Parshaker hydrogenator. The catalyst was filtered off with cerite and the filtrate was concentrated to give the desired crude product. The crude solid was suspended in iPrOH and reconcentrated. The resulting product was collected and then dried under high vacuum for 48 hours to give the desired product.

Preparation of compound B:
Following the basic procedure 2, compound A (27.2 g, 121.9 mmol) and 1,1,2-trichloroethane (35.8 g, 24.8 mL, 268.1 mmol) dissolved in methanol (800 mL) were prepared. Pershaker hydrogen containing Pd / C (10 wt%, 1.30 g, 1.22 mmol) and Pt / C (10 wt%, 2.38 g, 1.22 mmol) in 30 mL of H _{2 O under 70 psi H 2.} By shaking on the addition device, compound B (31.3 g, 97% over 2 steps) was obtained as a viscous pale yellow solid. ^{1 1} H NMR (500 MHz, CD ₃ OD) δ3.92-3.83 (m, 1H), 3.76-3.40 (m, 7H), 3.32-3.18 (m, 1H), 2 _{.99 (s, 3H), 1.52} (s, 9H); LC-MS: m / z calcd for C 11 H 23 N 3 O 2 [M + H] + 230.3, observed 230.2.

Preparation of compound C:
Ar-purged 5L RBF with stirring bar and 500mL funnel, compound B (23.4g, 87.8 mmol), Na ₂ CO ₃ (8.1 g, 82.4 mmol), and EtOH (2.0 L). Filled with. The resulting solution was stirred at room temperature for 1 hour. A solution of Fmoc-chloride (25.0 g, 4.76 mmol) in EtOH (700 mL) was added in droplets over 3 hours. The resulting solution was stirred at room temperature for 18 hours. The reaction was quenched with saturated Na ₂ CO ₃ solution (2.0 L) and brine (1.0 L). The aqueous layer was extracted with ethyl acetate (3 x 2.0 L), the organic extract was washed with brine (3 x 1.0 L), dried over ו ₄ and concentrated in vacuo. The crude yellow oil was purified by flash chromatography and then dried under vacuum overnight to give compound C (24.5 g, 62%) as a white solid. ^{1 1} H NMR (500MHz, CDCl ₃ ) δ7.77 (d, J = 7.6Hz, 2H), 7.57 (d, J = 7.5Hz, 2H), 7.40 (t, J = 7.5Hz) , 2H), 7.32 (t, J = 7.5Hz, 2H), 4.48-4.39 (m, 2H), 4.24 (t, J = 6.9Hz, 1H), 4.07 -3.82 (m, 2H), 3.43-2.79 (m, 9H), 2.79-2.54 (m, 2H), 1.46 (s, 9H); LC-MS: m / Z calcd for C ₂₆ H ₃₃ N ₃ O ₄ [M + H] ⁺ 452.6, observed 452.2.

Preparation of compound D:
Ar purged 250 mL round bottom flask with stirring bar and Ar inlet, capsaicin (2.82 g, 9.2 mmol), 4-nitrophenylchloroformate (1.95 g, 9.7 mmol), and acetonitrile (75 mL). ) Filled. The mixture was cooled to 0 ° C., N, N-diisopropylethylamine (4.8 mL, 27.6 mmol) was added and the mixture was stirred at 0 ° C. for 2 hours. Compound C (5.0 g, 11.1 mmol) and hydroxybenzotriazole 3H ₂ O (0.179 g, 0.92 mmol) were added to the reaction and the resulting solution was stirred at room temperature for 18 hours. The reaction was then diluted with 100 mL of ethyl acetate _{, washed with saturated NH 4} Cl solution (5 x 100 mL) and brine (3 x 100 mL), dried with silyl ₄ and concentrated in vacuo. The crude bright yellow oil was purified by flash chromatography to give compound D (3.89 g, 54%) as a pure white solid. ^{1 1} H NMR (500MHz, CDCl ₃ ) δ7.77 (d, J = 7.5Hz, 2H), 7.58 (d, J = 7.5Hz, 2H), 7.41 (t, J = 7.4Hz) , 2H), 7.33 (t, J = 7.5Hz, 2H), 7.09-6.94 (m, 1H), 6.90-6.73 (m, 2H), 5.81-5 .63 (m, 1H), 5.42-5.27 (m, 2H), 4.71-4.18 (m, 6H), 4.19-2.66 (m, 14H), 2.29 -2.15 (m, 3H), 1.99 (q, J = 7.0Hz, 2H), 1.65 (q, J = 7.5Hz, 2H), 1.54-1.33 (m, 11H), 0.95 (d, J = 6.8Hz, 6H); LC-MS: m / z calcd for C ₄₀ H ₅₁ N ₄ O ₆ [M-Boc + H] ⁺ 683.4, observed 683.3.

Basic procedure 3 (FMOC deprotection):
The RBF with a stir bar was filled _{with FMOC-protected intermediate and CH 2} Cl _2. Diethylamine was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude pale yellow oil was purified by flash chromatography to give the desired product.

Preparation of compound E:
Following the basic procedure 3, compound E (1) is formed as a foamy white solid by reacting compound D (3.89 g, 4.97 mmol) with _{CH 2} Cl _{2 (65 mL) and diethylamine (65 mL).} .78 g, 64%) was obtained. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ7.08-6.97 (m, 1H), 6.87 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.73 ( s, 1H), 5.43-5.25 (m, 2H), 4.45-4.17 (m, 3H), 4.08-3.65 (m, 5H), 3.49-3. 12 (m, 2H), 3.06-2.76 (m, 7H), 2.27-2.15 (m, 3H), 1.99 (q, J = 7.1Hz, 2H), 1. 82 (s, 1H), 1.65 (p, J = 7.7Hz, 2H), 1.52-1.35 (m, 11H), 0.95 (d, J = 6.8, 1.9Hz) , 6H); LC-MS: m / z calcd for C ₃₀ H ₄₉ N ₄ O ₆ [M + H] ⁺ 560.4, observed 561.3.

Basic procedure 4 (amide bond coupling with PEG-carboxylic acid):
Ar-purged flame-dried 100 mL RBF with a stir bar and Ar inlet was added to PEG-carboxylic acid, HATU (1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-]. b] Pyridinium 3-oxide hexafluorophosphate), and THF (50 mL). The solution was cooled to 0 ° C. in an ice bath and Ar was whipped throughout the solution over 10 minutes. Diisopropylethylamine (DIPEA) was then added and the reaction mixture was stirred at 0 ° C. After 2 hours, the starting material amine was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture is diluted with 75 _{mL of EtOAc, washed with saturated solution of NaHCO 3} (3 x 100 mL), _{saturated solution of NH 4} Cl (3 x 100 mL), brine (3 x 100 mL), dried with ו ₄ and in vacuo. Concentrated. The resulting crude material was purified by flash chromatography or preparative HPLC to give the desired product.

Preparation of compound F:
Following basic step 4, COOH-CM-PEG [3] -OMe (274 mg, 1.16 mmol), HATU (474 mg, 1.25 mmol), DIPEA (484 mg, 0.65 mL), to obtain crude compound F, 3.74 mmol) was reacted with compound E (500 mg, 0.89 mmol). This was purified by flash chromatography to obtain compound F (493 mg, 71%) as a transparent viscous oil. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ7.04 (s, 1H), 6.87 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.67 (s, 1H) , 5.42-5.28 (m, 2H), 4.70-4.45 (m, 2H), 4.40 (d, J = 5.5Hz, 2H), 4.24-3.85 ( m, 2H), 3.81 (s, 6H), 3.72-3.58 (m, 10H), 3.58-3.42 (m, 3H), 3.37 (s, 3H), 3 .31-2.59 (m, 8H), 2.30-1.11 (m, 3H), 1.99 (q, J = 6.9Hz, 2H), 1.73-1.62 (m, 2H), 1.52-1.30 (m, 11H), 0.95 (d, J = 6.7Hz, 6H); LC-MS: m / z calcd for C ₄₀ H ₆₇ N ₄ O ₁₁ [M + H ] ⁺ 779.5, observed 779.4.

Basic procedure 5 (Boc deprotection):
Ar-purged flame-dried RBF with a stir bar and Ar inlet _{was filled with Boc-protected prodrug and Et 2} O (20 mL). The solution was cooled to 0 ° C. in an ice bath and Ar was whipped throughout the stirred solution. After purging the solution with Ar for 20 minutes, the solution of HCl in Et ₂ O (2.0 M, 20 mL) was transferred to the stirred solution by a syringe. After adding ethereal HCl, the solution quickly turned milky white and gradually became clear as the material deposited on the sides of the flask. The reaction mixture was concentrated in vacuo and placed under high vacuum for 12 hours. The crude product was then dissolved in a minimum amount of CH ₂ Cl ₂ and slowly added to a centrifuge tube containing hexane / Et ₂ O (50 mL, 1: 1). The resulting highly viscous off-white precipitate was centrifuged to pellet and the supernatant was decanted. The product was dissolved and precipitated three more times to give a pure prodrug.

Preparation of compound 1:
Following basic procedure 5, compound F (442 mg, 0.57 mmol) was converted to compound 1 (fluid off-white powder, 388 mg, 96%). ^{1 1} H NMR (500 MHz, CD ₃ OD) δ7.10 (s, 1H), 7.05 (s, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.43-5.32 (M, 2H), 4.86-4.02 (m, 6H), 3.91-3.75 (m, 5H), 3.73-3.48 (m, 13H), 3.48-3 .34 (m, 5H), 3.29-2.89 (m, 3H), 2.87-2.75 (m, 3H), 2.61-2.45 (m, 1H), 2.29 -2.17 (m, 3H), 2.01 (q, J = 6.8Hz, 2H), 1.65 (p, J = 7.5Hz, 2H), 1.39 (p, J = 7. 5Hz, 2H), 0.97 (d, J = 6.7Hz, 6H); LC-MS: m / z calcd for C ₃₅ H ₅₉ N ₄ O ₉ [M + H] ⁺ 679.4, observed 679.4.

Example 2: (E) -2-Methoxy-4-((8-methylnon-6-enamide) methyl) phenyl) 2-((Methylamino) methyl) -4- (2,5,8,11,14) , 17,20-Hetaoxatricosan-23-oil) Synthesis of piperazine-1-carboxylate (Compound 2)

Preparation of compound G:
Following basic step 4, COOH-CM-PEG [6] -OMe (400 mg, 1.09 mmol), HATU (445 mg, 1.17 mmol), DIEA (466 mg, 0.63 mL), to obtain crude compound G, 3.60 mmol) was reacted with compound E (507 mg, 0.90 mmol). This was purified by flash chromatography to obtain compound G (716 mg, 87%) as a transparent viscous oil. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ7.09-6.95 (m, 1H), 6.87 (s, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.70 ( s, 1H), 5.41-5.27 (m, 2H), 4.70-4.43 (m, 2H), 4.40 (d, J = 5.5Hz, 2H), 4.19- 3.86 (m, 2H), 3.86-3.71 (m, 6H), 3.65 (s, 22H), 3.57-3.44 (m, 3H), 3.37 (s, 3H), 3.31-2.62 (m, 8H), 2.26-2.18 (m, 3H), 1.99 (q, J = 7.0Hz, 2H), 1.65 (t, J = 7.8Hz, 2H), 1.52-1.32 (m, 11H), 0.94 (d, J = 6.8Hz, 6H); LC-MS: m / z calcd for C ₄₆ H ₇₉ N ₄ O ₁₄ [M + H] ⁺ 911.6, observed 911.5.

Preparation of compound 2:
Following basic procedure 5, compound G (665 mg, 0.73 mmol) was converted to compound 2 (viscous pale yellow oil, 535 mg, 89%). ^{1 1} H NMR (500 MHz, CD ₃ OD) δ7.15-7.01 (m, 2H), 6.94-6.86 (m, 1H), 5.44-5.32 (m, 2H), 4 .84-4.44 (m, 2H), 4.38 (s, 2H), 4.33-4.08 (m, 2H), 3.90-3.36 (m, 35H), 3.31 -2.94 (m, 3H), 2.91-2.77 (m, 3H), 2.45-2.30 (m, 1H), 2.30-2.15 (m, 3H), 2 .02 (q, J = 6.8Hz, 2H), 1.65 (p, J = 7.5Hz, 2H), 1.40 (p, J = 7.6Hz, 2H), 0.97 (d, J = 6.8Hz, 6H); LC-MS: m / z calcd for C ₄₁ H ₇₁ N ₄ O ₁₂ [M + H] ⁺ 811.5, observed 811.4.

Example 3: (E) -2-Methoxy-4-((8-methylnon-6-enamide) methyl) Phenyl 4- (2,5,8,11,14,17,20,23,26,29-) Synthesis of decaoxadotriacontane-32-oil) -2-((methylamino) methyl) piperazine-1-carboxylate (Compound 3)

Preparation of compound G:
Following basic step 4, COOH-CM-PEG [9] -OMe (400 mg, 0.80 mmol), HATU (331 mg, 0.87 mmol), DIPEA (347 mg, 0.47 mL), to obtain crude compound H, 2.68 mmol) was reacted with compound E (373 mg, 0.67 mmol). This was purified by HPLC to give compound H (519 mg, 74%) as a transparent viscous oil. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ7.08-6.91 (m, 1H), 6.86 (s, 1H), 6.81 (d, J = 7.6Hz, 1H), 5.83 ( s, 1H), 5.40-5.24 (m, 2H), 4.71-4.42 (m, 2H), 4.37 (d, J = 5.6Hz, 2H), 4.19- 3.84 (m, 2H), 3.79 (s, 6H), 3.63 (s, 34H), 3.55-3.40 (m, 3H), 3.35 (s, 3H), 3 .32-2.53 (m, 8H), 2.25-2.15 (m, 3H), 1.97 (q, J = 7.0Hz, 2H), 1.63 (p, J = 7. 7Hz, 2H), 1.48-1.33 (m, 11H), 0.93 (d, J = 6.7Hz, 6H); LC-MS: m / z calcd for C ₅₂ H ₉₁ N ₄ O ₁₇ [M + H] ⁺ 1043.6, observed 1043.5.

Preparation of compound 3:
Ar-purged flame-dried 100 mL RBF with a stir bar and Ar inlet was filled with compound H (463 mg, 0.44 mmol) and methanolic HCl (3M, 50 mL). The solution was warmed to 40 ° C. in an oil bath and stirred for 2 hours. The reaction mixture was concentrated in vacuo and placed under high vacuum for 12 hours. The crude product was then dissolved in a minimum amount of CH ₂ Cl ₂ and slowly added to a centrifuge tube containing hexane / Et ₂ O (50 mL, 1: 1). The resulting highly viscous off-white precipitate was centrifuged to pellet and the supernatant was decanted. The product was dissolved and precipitated three more times to give compound 3 (391 mg, 91%) as a viscous yellow oil. ^{1 1} H NMR (600 MHz, CD ₃ OD) δ7.13-7.01 (m, 2H), 6.94-6.86 (m, 1H), 5.43-5.32 (m, 2H), 4 .80-4.53 (m, 2H), 4.37 (s, 2H), 4.31-4.07 (m, 2H), 4.01-3.40 (m, 44H), 3.36 (S, 3H), 3.29-3.02 (m, 3H), 2.92-2.79 (m, 3H), 2.44-2.30 (m, 1H), 2.30-2 .18 (m, 3H), 2.01 (q, J = 6.9Hz, 2H), 1.64 (p, J = 7.6Hz, 2H), 1.39 (p, J = 7.5Hz, 2H), 0.97 (d, J = 6.7Hz, 6H); LC-MS: m / z calcd for C ₄₇ H ₈₃ N ₄ O ₁₅ [M + H] ⁺ 943.6, observed 943.4.

Example 4: (E) -2-Methoxy-4-((8-methylnon-6-enamide) methyl) Phenyl 4- (2,5,8,11,14,17,20,23,26,29, Synthesis of 32,35,38-tridecaoxahentetracontane-41-oil) -2-((methylamino) methyl) piperazine-1-carboxylate (Compound 4)

Preparation of compound I:
Following basic step 4, COOH-CM-PEG [12] -OMe (400 mg, 0.63 mmol), HATU (262 mg, 0.69 mmol), DIEA (274 mg, 0.37 mL), to obtain crude compound I, 2.12 mmol) was reacted with compound E (295 mg, 0.53 mmol). This was purified by HPLC to give compound I (338 mg, 54%) as a transparent viscous oil. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ7.09-6.95 (m, 1H), 6.87 (s, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.10 ( s, 1H), 5.41-5.25 (m, 2H), 4.76-4.46 (m, 2H), 4.41 (s, 2H), 4.27-3.90 (m, 2H), 3.81 (s, 6H), 3.64 (s, 46H), 3.58-3.47 (m, 3H), 3.37 (s, 3H), 3.36-2.60 (M, 8H), 2.27 (t, J = 7.7Hz, 2H), 2.25-2.16 (m, 1H), 1.98 (q, J = 7.1Hz, 2H), 1 .64 (p, J = 7.7Hz, 2H), 1.52-1.33 (m, 11H), 0.94 (d, J = 6.8Hz, 6H); LC-MS: m / z calcd for C ₅₃ H ₉₅ N ₄ O ₁₈ [M-Boc + 2H] ⁺ 1075.7, observed 1075.6.

Preparation of compound 4:
Following basic procedure 5, compound I (303.5 mg, 0.26 mmol) was converted to compound 4 (viscous yellow oil, 214 mg, 75%). ^{1 1} H NMR (600 MHz, CD ₃ OD) δ7.14-7.02 (m, 2H), 6.94-6.87 (m, 1H), 5.43-5.33 (m, 2H), 4 .76-4.58 (m, 2H), 4.38 (s, 2H), 4.33-4.16 (m, 2H), 4.16-3.40 (m, 56H), 3.37 (S, 3H), 3.29-3.08 (m, 3H), 2.91-2.80 (m, 3H), 2.45-2.32 (m, 1H), 2.29-2 .20 (m, 3H), 2.01 (q, J = 6.8Hz, 2H), 1.65 (p, J = 7.5Hz, 2H), 1.40 (p, J = 7.5Hz, 2H), 0.97 (d, J = 6.7Hz, 6H); LC-MS: m / z calcd for C ₅₃ H ₉₅ N ₄ O ₁₈ [M + H] ⁺ 1075.7, observed 1075.4.

Example 5: Synthesis of (E) -2-methoxy-4-((8-methylnon-6-enamide) methyl) phenyl) 2-((methylamino) methyl) piperazine-1-carboxylate (Compound 5)

Ar-purged flame-dried 50 mL RBF with a stir bar and Ar inlet was filled with compound E (150 mg, 0.27 mmol) and methanolic HCl (3M, 20 mL). The solution was warmed to 40 ° C. in an oil bath and stirred for 5 hours. The reaction mixture was concentrated in vacuo and placed under high vacuum for 12 hours. The crude product was then dissolved in a minimum amount of CH ₂ Cl ₂ and slowly added to the centrifuge tube containing Et _{2 O (50 mL).} The resulting off-white precipitate was centrifuged to pellet and the supernatant was decanted. The product was dissolved and precipitated three more times to give compound 5 (103 mg, 77%) as an off-white solid. ^{1 1} H NMR (500 MHz, CD ₃ OD) δ7.15 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5 .44-5.33 (m, 2H), 5.13-4.96 (m, 1H), 4.63-4.21 (m, 4H), 3.89 (s, 4H), 3.66 -3.42 (m, 4H), 3.38-3.35 (m, 1H), 3.31-3.20 (m, 1H), 2.85 (s, 3H), 2.30-2 .19 (m, 3H), 2.02 (q, J = 6.8Hz, 2H), 1.65 (p, J = 7.6Hz, 2H), 1.40 (p, J = 7.5Hz, 2H), 0.98 (d, J = 6.8Hz, 6H); LC-MS: m / z calcd for C ₂₅ H ₄₁ N ₄ O ₄ [M + H] ⁺ 461.3, observed 461.3.

Example 6: (E) -2-methoxy-4-((8-methylnon-6-enamide) methyl) phenyl 4-methyl-2-((methylamino) methyl) piperazine-1-carboxylate (Compound 6) Synthesis of

Preparation of compound I:
Ar purged 50 mL round bottom flask with stirring bar and Ar inlet filled with compound E (200 mg, 0.36 mmol), triethylamine (44 mg, 0.06 mL, 0.43 mmol), CH ₂ Cl ₂ (20 mL). , Cooled to 0 ° C. in an ice bath. After stirring for 10 minutes, iodomethane (511 mg, 0.22 mL, 3.60 mmol) was added and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude material was purified by flash chromatography to give compound J as an off-white solid. LC-MS: m / z calcd for C ₃₁ H ₅₁ N ₄ O ₆ [M + H] ⁺ 575.4, observed 575.4.

Preparation of compound 6:
Ar-purged flame-dried 50 mL RBF with a stir bar and Ar inlet was filled with Intermediate J (206.6 mg, 0.36 mmol) and methanolic HCl (3M, 20 mL). The solution was warmed to 40 ° C. in an oil bath and stirred for 18 hours. The reaction mixture was concentrated in vacuo and placed under high vacuum for 12 hours. The crude product was then dissolved in a minimum amount of EtOH _{and slowly added to a centrifuge tube containing Et 2} O / hexane (50 mL, 1: 1). The resulting off-white precipitate was centrifuged to pellet and the supernatant was decanted. The product was dissolved and precipitated three more times to give compound 6 (89.7 mg, 52% over two steps) as an off-white solid. ^{1 1} H NMR (500 MHz, CD ₃ OD) δ7.14 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5 .44-5.33 (m, 2H), 5.18-4.93 (m, 1H), 4.62-4.40 (m, 2H), 4.38 (s, 2H), 4.00 -3.81 (m, 4H), 3.66 (dd, J = 50.3, 13.1Hz, 3H), 3.52-3.44 (m, 1H), 3.30-3.14 ( m, 3H), 2.99 (s, 3H), 2.86 (d, J = 24.7Hz, 3H), 2.31-2.18 (m, 3H), 2.02 (q, J = 6.8Hz, 2H), 1.65 (p, J = 7.7Hz, 2H), 1.40 (p, J = 7.5Hz, 2H), 0.98 (dd, J = 6.8, 1) .8Hz, 6H); LC-MS: m / z calcd for C ₂₆ H ₄₃ N ₄ O ₄ [M + H] ⁺ 475.3, observed 475.3.

Example 7: (E) -2-methoxy-4-((8-methylnon-6-enamide) methyl) phenyl 4-acetyl-2-((methylamino) methyl) piperazine-1-carboxylate (Compound 7) Synthesis of

Preparation of compound L:
An Ar-purged 100 mL round-bottom flask equipped with a stirring bar and an Ar inlet _{was filled with compound E (500 mg, 0.89 mmol), CH 2} Cl ₂ (40 mL) and cooled to 0 ° C. in an ice bath. Triethylamine (99.3 mg, 0.14 mL, 0.98 mmol) was added and the resulting solution was stirred for 10 minutes. Acetyl chloride (84.0 mg, 0.076 mL, 1.07 mmol) was then added and stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated in vacuo and the crude off-white solid was purified by flash chromatography to give compound L (464 mg, 87%) as a white solid. ^{1 1} H NMR (500 MHz, CDCl ₃ ) δ7.08-6.94 (m, 1H), 6.87 (s, 1H), 6.81 (d, J = 7.7 Hz, 1H), 5.82 ( s, 1H), 5.41-5.26 (m, 2H), 4.72-4.42 (m, 2H), 4.38 (d, J = 5.5Hz, 2H), 4.21- 4.02 (m, 1H), 3.88-3.57 (m, 5H), 3.56-2.73 (m, 7H), 2.25-2.09 (m, 6H), 1. 98 (q, J = 7.0Hz, 2H), 1.64 (p, J = 7.7Hz, 2H), 1.50-1.34 (m, 11H), 0.94 (d, J = 6) .8, 1.6Hz, 6H); LC-MS: m / z calcd for C ₃₂ H ₅₁ N ₄ O ₇ [M + H] ⁺ 603.4, observed 603.4.

Preparation of compound 7:
Following basic procedure E, compound L (414 mg, 0.69 mmol) was converted to compound 7 (fluid off-white powder, 362 mg, 98%). ^{1 1} H NMR (500 MHz, CD ₃ OD) δ7.10 (d, J = 8.1 Hz, 1H), 7.04 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5 .42-5.31 (m, 2H), 4.85-4.55 (m, 1H), 4.53-4.40 (m, 1H), 4.37 (s, 2H), 4.32 -4.11 (m, 1H), 3.96 (s, 1H), 3.91-3.77 (m, 3H), 3.69-3.34 (m, 3H), 3.15 (td) , J = 13.2,12.7, 4.3Hz, 2H), 2.86-2.69 (m, 3H), 2.31-2.11 (m, 6H), 2.00 (q, J = 6.8Hz, 2H), 1.64 (p, J = 7.7Hz, 2H), 1.38 (p, J = 7.5Hz, 2H), 0.96 (d, J = 6.8Hz) , 6H); LC-MS: m / z collected for C ₂₇ H ₄₃ N ₄ O ₅ [M + H] ⁺ 503.3, observed 503.3.

Example 8: (E) -4-ethyl 1- (2-methoxy-4-((8-methylnon-6-enamide) methyl) phenyl) 2-((methylamino) methyl) piperazine-1,4-di Synthesis of carboxylate (Compound 8)

Preparation of compound K:
An Ar-purged 25 mL round-bottom flask equipped with a stirring bar and an Ar inlet _{was filled with compound E (150 mg, 0.27 mmol), CH 2} Cl ₂ (15 mL) and cooled to 0 ° C. in an ice bath. Triethylamine (32 mg, 45 μL, 0.32 mmol) was added and the resulting solution was stirred for 10 minutes. Ethyl chloroformate (32 mg, 28 μL, 0.30 mmol) was then added and stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated in vacuo and compound K was used as a light, soft off-white solid without further purification.

Preparation of compound 8:
Ar-purged flame-dried 25 mL RBF with a stir bar and Ar inlet was filled with compound K (170.9 mg, 0.27 mmol) and methanolic HCl (3M, 10 mL). The solution was warmed to 40 ° C. in an oil bath and stirred for 1 hour. The reaction mixture was concentrated in vacuo and placed under high vacuum for 12 hours. The crude product was then dissolved in a minimum amount of EtOH _{and slowly added to a centrifuge tube containing Et 2} O / hexane (50 mL, 1: 1). The resulting white precipitate was centrifuged to pellet and the supernatant was decanted. The product was dissolved and precipitated three more times to give compound 8 (155 mg, <99%) over two steps as a white solid. ^{1 1} H NMR (500 MHz, CD ₃ OD) δ7.11 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.96-6.87 (m, 1H), 5.46 -5.33 (m, 2H), 4.65 (s, 1H), 4.38 (s, 2H), 4.32-4.02 (m, 5H), 3.92-3.83 (m) , 3H), 3.57 (s, 2H), 3.29-3.17 (m, 3H), 2.91-2.71 (m, 3H), 2.31-2.19 (m, 3H) ), 2.02 (q, J = 6.9Hz, 2H), 1.66 (p, J = 7.6Hz, 2H), 1.45-1.38 (m, 2H), 1.33 (dt) , J = 10.9, 7.1Hz, 3H), 0.98 (d, J = 6.6Hz, 6H); LC-MS: m / z calcd for C ₂₈ H ₄₅ N ₄ O ₆ [M + H] ⁺ 533.3, observed 533.3.

In vitro Assay Example 9: Solubility Assay To determine the water solubility of the compounds described herein, the HCl salts of the following compounds are incubated in DI water at 50 or 100 mg / mL and the undissolved material is visually inspected. bottom.

Example 10: In vitro (pH Stability) Assay The release of the parent drug (eg, capsaicin) from the compounds described herein is demonstrated by stability testing of multiple compounds. The compounds described herein are examples in which the half-life of an intramolecular cyclization-release reaction is required when exposed to a specific pH by activating the pH of the prodrug. This intramolecular cyclization release reaction results in the simultaneous formation of cyclic urea by the release of the parent drug.

Compounds were incubated in the indicated buffer / biological medium. The reaction was carried out at room temperature or 37 ° C. In some embodiments, additional common ingredients / formulations that can be used in the buffer to test the cyclized release of the compounds described herein include, but are not limited to: N- (. 2-Acetamide) -2-aminoethanesulfonic acid, N- (2-acetamide) imino2acetic acid, 2-amino-2-methyl-1,3-propanediol, bicarbonate, N, N-bis (2-) Hydroxyethyl) glycine, 2-bis (2-hydroxyethyl) amino-2- (hydroxymethyl) -1,3-propanediol, 3- (cyclohexylamino) -1-propanesulfonic acid, 2- (cyclohexylamino) ethane Sulphonic acid, carbonate, citrate, 4- (2-hydroxyethyl) -1-piperazin propanesulfonic acid, glycine salt, 4- (2-hydroxyethyl) piperazin-1-ethanesulfonic acid, 4-morpholinethan sulfonate Acid, 4-morpholine propanesulfonic acid, 1,4-piperazindietanesulfonic acid, phosphate, tartrate, 2-[(2-hydroxy-1,1-bis (hydroxymethyl) ethyl) amino] ethanesulfonic acid , And EDTA salt.

Samples are collected at specific time points and quenched with a solution of 1.0% TFA in acetonitrile to stop the cyclization release reaction and by HPLC the formation of released capsaicin, by-products of cyclic urea, and plasma and cerebrospinal fluid. The consumption of starting compounds in liquid (CSF) was analyzed. As shown in Table 1, both acylated prodrugs (Compound 1, Compound 2, Compound 3, Compound 4, Compound 7, Compound 8) and non-acylated prodrugs (Compound 5, Compound 6) are simulated. Demonstrated rapid intramolecular cyclization release under physiologic conditions (ie, all prodrugs demonstrated conversion half to capsaicin at pH 7.4 and 37 ° C. for less than 5 minutes). However, as shown in Table 2, the acylated piperazine prodrug (Compound 1, Compound 2, Compound 3, Compound 7, Compound 8) is a non-acylated prodrug (Compound 6) at pH 4.5 and room temperature (RT). It was demonstrated that the stability was significantly and unexpectedly increased compared to the above. Therefore, since the acylated piperazine prodrugs described herein have demonstrated increased stability of the solution state at pH 4.5, these prodrugs result in a substantial conversion to a powerful drug (ie, capsaicin). It may provide a reasonable time frame (eg 0-4 hours) for retention / manipulation of the predrug dose formulation without administration.

Pharmacokinetics Example 11: Plasma & CSF time course of test compound after epidural administration to rats Epidural administration: Compounds 1 to 4 and compound 7 are dissolved in sterile water for injection and the pH is 4. It was prepared in 5 and administered to male Sprague dolly rats by epidural injection. Compound 1, Compound 4, and Compound 7 were administered at 1 mg / kg body weight, added, and molar-corrected to an equimolar concentration. At specific time points, blood samples (0.25 mL) are collected from the jugular vein cannula and placed in a tube containing K2EDTA as an anticoagulant and 10 μL (pH 3.0) of 2.5 M citrate buffer as a stabilizer. It was added to prevent prodrug conversion in Exvivo and treated against plasma. Plasma samples were taken from each rat before and 10 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after administration. At a specific point in time, a CSF sample (0.05 mL) is collected by CM tap _{and contains K 2} EDTA as an anticoagulant and 10 μL (pH 3.0) of 2.5 M citrate buffer as a stabilizer. I put it in and prevented the prodrug conversion in Exvivo. CSF samples were taken from each rat before and 10 minutes, 30 minutes and 1 hour after administration. The plasma and CSF concentrations of the test compound fluctuating capsaicin and / or the resulting cyclic urea were determined and are shown in FIGS. 1, 2, and 3. As shown in FIG. 3, the resulting cyclic urea showed differential CSF penetration over the observed time lapse. The cyclic urea of Compound 1 showed that when the corresponding prodrug was administered epidurally to rats at equimolar doses, the resulting amount of cyclic urea CSF exposure was minimal on a molar basis.

The embodiments and embodiments described herein are for illustration purposes only, and in some embodiments, various modifications or modifications are within the scope of this disclosure and the accompanying claims. It shall be.

Claims (43)

A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a hydrate.

During the ceremony
Y is a phenolic TRPV1 agonist, where the hydrogen atom of the phenolic hydroxyl group is

Replaced by a covalent bond with
R ₁ is hydrogen or C _1- C ₆ alkyl,
R ₂ is-(CH _{2 CH 2} O) _n R ₃ , -C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R ₃ , -C (O) O (CH ₂ CH ₂ O) ) _N R ₃ , -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R ₃ , -C (O) R ₅ , -C (O) OR ₅ , or -C (O) N ( R ₄ ) (R ₅ ),
R ₃ is hydrogen or C _1- C ₆ alkyl,
R ₄ is hydrogen or _C 1 -C ₆ alkyl,
R ₅ is C _1- C ₅₀ alkyl and is
m is 1 to 10
A compound in which n is 1 to 50 and p is 1-9. R _{2 is, -CH 2 CH 2 O n R} 3, -C (O) (CH 2) m O (CH 2 CH 2 O) n R 3, -C (O) O (CH 2 CH 2 O) n The compound according to claim 1, wherein R ₃ or -C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R _3. The compound according to claim 1 or 2, wherein R ₂ is −C (O) (CH ₂ ) _m O (CH ₂ CH ₂ O) _n R _3. The compound according to any one of claims 1 to 3, wherein m is 1 to 5. The compound according to any one of claims 1 to 4, wherein m is 2. The compound according to claim 1 or 2, wherein R ₂ is − (CH ₂ CH ₂ O) _n R _3. The compound according to claim 1 or 2, wherein R ₂ is −C (O) O (CH ₂ CH ₂ O) _n R _3. The compound according to claim 1 or 2, wherein R ₂ is −C (O) N (R ₄ ) (CH ₂ CH ₂ O) _n R _3. R ₄ is hydrogen The compound of claim 8. The compound according to claim 8, wherein R ₄ is C _1- C _{6 alkyl.} The compound according to any one of claims 1 to 10, wherein R _{3 is hydrogen.} The compound according to any one of claims 1 to 10, wherein R ₃ is C _1- C _{6 alkyl.} The compound according to claim 12, wherein R ₃ is −CH _3. The compound according to any one of claims 1 to 13, wherein n is 1 to 30. The compound according to any one of claims 1 to 14, wherein n is 2 to 20. The compound according to any one of claims 1 to 15, wherein n is 2 to 12. The compound according to any one of claims 1 to 16, wherein n is 4 to 10. The compound according to claim 1, wherein R ₂ is −C (O) R _5. The compound according to claim 1, wherein R ₂ is −C (O) OR _5. The compound according to claim 1, wherein R ₂ is −C (O) N (R ₄ ) (R _5). The compound according to any one of claims 18 to 20, wherein R ₅ is C _1- C _{25 alkyl.} The compound according to any one of claims 18 to 21, wherein R ₅ is C _1- C _{10 alkyl.} The compound according to any one of claims 18 to 22, wherein R ₅ is C _1- C _{5 alkyl.} 23. The compound of claim 23, wherein R ₅ is −CH _3. The compound according to any one of claims 1 to 24, wherein R ₁ is C _1- C _{6 alkyl.} The compound according to any one of claims 1 to 25, wherein R ₁ is C _1- C _{3 alkyl.} The compound according to any one of claims 1 to 26, wherein R ₁ is −CH _3. The compound according to any one of claims 1 to 26, wherein R ₁ is −CH ₂ CH _3. The compound according to any one of claims 1 to 24, wherein R _{1 is hydrogen.} The compound according to any one of claims 1 to 29, wherein p is 1. The compound according to any one of claims 1 to 29, wherein p is 2. Y is

R ₆ is independently hydrogen, halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC. _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl, C _1- C ₆ fluoroalkyl , C _1- C ₆ heteroalkyl, C _1- C ₆ alkoxy, C _1- C ₆ fluoroalkoxy, C _2- C ₉ heterocycloalkyl, C _6- C ₁₀ aryl, C _1- C ₉ heteroaryl, C ₆ -C _{10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl _sulfoxide, C 6 _{-C 10} aryl _sulfoxide, C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} Selected from aryl sulfones, J is -NHC (O) R ₇ or -C (O) OR ₇ , and R ₇ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N ( CH ₃ ) ₂ , -OH, -CO ₂ H, -C (O) OC _1- C ₆ alkyl, -C (O) NH ₂ , -C (O) NH (C _1- C ₆ alkyl), -C (O) N (C _1- C ₆ alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ NH (C _1- C ₆ alkyl), -SO ₂ N (C _1- C ₆ alkyl) ₂ , C _1- C ₆ alkyl, C ₃ −C ₈ cycloalkyl, C _{1 −} C ₆ fluoroalkyl, C _{1 −} C ₆ heteroalkyl, C _{1 −} C ₆ alkoxy, C _{1 −} C ₆ fluoroalkoxy, C _{2 −} C ₉ heterocyclo _alkyl, C 6 _{-C 10 aryl,} C 1 -C _{9 heteroaryl,} C 6 _{-C 10 aryloxy,} C 1 -C _{6 alkylthio,} C 6 _{-C 10 arylthio,} C 1 -C ₆ alkyl sulfoxide, _{C 6} - C ₁₀ aryl _{sulfoxide, C} 1 -C ₁ being optionally substituted with C 1 -C ₆ alkylsulfonate, and _C 6 _{-C 10} 1 or more groups selected from arylsulfonic It is a ₂ alkyl A compound according to any one of claims 1 to 31. 32. The compound of claim 32, wherein J is −NHC (O) R _7. The compound according to claim 32, wherein J is −C (O) OR _7. The compound according to any one of claims 32 to 34, wherein R ₇ is an unsubstituted C _1- C _{12 alkyl.} R ₆ is _C 1 -C ₆ alkoxy, A compound according to any one of claims 32 35. Y is

The compound according to any one of claims 1 to 31. Y is

37. The compound according to claim 37. A compound having the following structure, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a hydrate.

A compound having the following structure, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate, or a hydrate.

A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate or hydrate, and a pharmaceutically acceptable diluent. A pharmaceutical composition comprising an excipient or a binder. A method of treating a subject's pain, wherein the method is a therapeutically effective amount of the compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable. A method comprising the step of administering an acceptable solvate or hydrate to said subject. 42. The method of claim 42, wherein the pain is associated with cancer.

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